Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001427864
Ethics application status
Approved
Date submitted
2/09/2021
Date registered
21/10/2021
Date last updated
23/09/2022
Date data sharing statement initially provided
21/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Understanding the profile of midazolam administered using the NasoSURF device to healthy volunteers
Scientific title
Pharmacokinetics and pharmacodynamics of midazolam administered intranasally using the NasoSURF device to healthy volunteers
Secondary ID [1] 304989 0
AFT-MD-04
Universal Trial Number (UTN)
U1111-1269-1743
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Conscious Sedation
 323143 0
Condition category
Condition code
Anaesthesiology 320717 320717 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will be randomly allocated to a sequence to receive during each study period either a single dose of the intervention treatments or the comparator treatment in a two-way crossover sequence.

Intervention:
Treatment B: Midazolam 2.5 mg/kg (500 µL of 5mg/mL solution) delivered as a single dose intranasally using the NasoSURF Med device

Administration:
500µL of 5mg/mL midazolam solution for injection (effective dose 2.5mg) will be administered intranasally using the NasoSURF device (using continuous delivery mode – 0 Hz) into alternating nostrils over up to approximately 4 - 6 breath cycles.
Participants will hold the device to self-administer while under nurse or doctor supervision. The nose-piece of the device will be inserted gently into one nostril at a time, and participants will exhale into the mouthpiece. Upon exhalation into the mouthpiece, the device will aerosolize the midazolam and administer ~125 µL of midazolam per breath-cycle via the nose-piece. The participant should alternate nostrils for each breath-cycle until all of the midazolam in the medicine unit of the device has been administered. During administration of midazolam with the NasoSURF device the participant’s head must be positioned in a straight and upright position.

The time of administration will be documented.

There will be a washout period of at least 48 hours between treatment periods.
Intervention code [1] 321379 0
Treatment: Drugs
Intervention code [2] 321380 0
Treatment: Devices
Comparator / control treatment
Comparator
Treatment A: Midazolam 2.5 mg/kg (500 µL of 5mg/mL solution) delivered as a single dose intravenously.

Administration:
500µL of 5mg/mL midazolam solution for injection (effective dose 2.5mg) will be infused over a 1-minute period (at a rate of 500µL/min).

Time of administration will be recorded.
Control group
Active

Outcomes
Primary outcome [1] 328538 0
Describe the pharmacokinetic profile of a 2.5mg dose of midazolam (MDZ) administered intranasally using the NasoSURF device, compared to 2.5mg MDZ administered intravenously.

MDZ pharmacokinetic parameters will be derived from the plasma
concentration vs. time data using non-compartmental methods, and will include the
following:
- Cmax
- Tmax
- AUC0-t
- AUC0-8
- t1/2
- kel
The Cmax, AUC0-t and AUC0-8 of 1-hydroxymidazolam (primary metabolite of MDZ) will also be assessed.
Timepoint [1] 328538 0
For both treatments (A and B), blood samples will be drawn at pre-dose, immediately following administration, 2, 5, 10, 15, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours after the end of administration.
Primary outcome [2] 329125 0
Determine the relative bioavailability of MDZ administered via the NasoSURF device compared to intravenous administration.

Pharmacokinetic and bioavailability assessments will be performed on log(e) transformed
AUC0-t, AUC0-8, and Cmax data to obtain geometric means for each treatment.
Timepoint [2] 329125 0
For both treatments (A and B), blood samples will be drawn at pre-dose, immediately following administration, 2, 5, 10, 15, 20, 30, 45 minutes and 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours after the end of administration.
Secondary outcome [1] 399357 0
Explore the extent and rate (composite outcome) of sedation using the Observers Assessment of Alertness/Sedation (OAA/S) sedation scale after midazolam is administered using either the NasoSURF device and intravenously.
Timepoint [1] 399357 0
OAA/S assessments will be performed immediately following the completion of the pharmacokinetic blood sampling which is taken at times: pre-dose, 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 2, 3, 4, 6, and 8 hours post-dose.
Secondary outcome [2] 399358 0
To examine the safety and tolerability of MDZ administered using either the NasoSURF device or intravenously. This includes spontaneously reported treatment-emergent adverse events (TEAEs), changes in blood hematology and biochemistry, and vital signs (blood pressure, heart rate, temperature (aural/tympanic), respiratory rate).

Side effects that have previously been reported due to the intranasal or intravenous administration of Midazolam include the following:
respiratory depression (slow or ineffective breathing), apnoea (temporary pause in breathing), variations in blood pressure and pulse rate, local effects at the intravenous site: tenderness, pain during injection, hiccups, redness, nausea, vomiting, coughing, induration (area of hardness in the skin), drowsiness, oversedation, phlebitis (inflammation of a vein)

• Midazolam causes “anterograde amnesia” which is the lack of ability to form memories, the duration of which is directly related to the administered dose.

• Behavioural reactions to Midazolam such as restlessness, agitation, irritability, involuntary movements, hyperactivity, combativeness, delusion, anger, anxiety, nightmares, hallucinations, psychoses, inappropriate behaviour, hostility, rage reaction, aggression, paroxysmal excitement and assault or other adverse behavioural effects have been reported.

Possible Side Effects of Intravenous Drug Administration and Blood Collection:
The study staff will collect the participants' blood by a needle placed in a vein. They may experience some discomfort during this procedure including: Pain at the site of needle stick, Bruising, Dizziness

Possible Side Effects of Intranasal Drug Administration
The NasoSURF Med device is an “investigational” device which means this product has not been approved by the regulatory authority but is available in a study like this one. Not all of the adverse device related events are known. Participants may experience mild nasal irritation due to the intranasal administration of Midazolam using the NasoSURF Med device.
Timepoint [2] 399358 0
Acute safety evaluation will be performed during each study period by recording spontaneously reported treatment-emergent adverse events (TEAEs), and any changes in vital signs.

Adverse events (AEs) will continue to be assessed up to 7 days after the last dose of study medication by spontaneous reporting and at a final follow-up phone call on day 7 post last dose.

At the end of each study period an additional blood sample will be taken for haematology and biochemistry assessments.

Eligibility
Key inclusion criteria
Partipicants may be eligible for this study if they meet the following inclusion criteria
• Male and female volunteers aged between 18 and 60 years, inclusive, on the day of consent.
• Voluntarily provide written informed consent before the initiation of any study-related procedures.
• Have a Body Mass Index (BMI) between 18.0 and 32.0 kg/m2.
• Have no significant disease (cardiac, pulmonary, GI, hepatic, renal, haematological, neurological (including sleep disorders), infective, or psychiatric) as determined by medical history, physical examination and laboratory tests as determined by the Principal Investigator.
• Be able and willing to abstain from caffeine-containing beverages (e.g. coffee, soda, or tea), caffeine-containing food (e.g. chocolate), and alcohol for 24 hours prior to study drug administration until after the last study sample is collected in each dosing period.
• Be able and willing to abstain from all prescription and over-the-counter medications (excluding the study drug and oral contraceptive) and herbal medicines/supplements for the duration of the study as determined by the Principal Investigator.
• Have a normal 12-lead ECG or one with an abnormality considered to be clinically insignificant as determined by the Principal Investigator.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants will not be eligible for inclusion in this study if any of the following criteria are met:

• Women who are pregnant or nursing.
• Women of childbearing potential who are unwilling to take adequate contraceptive precautions, i.e., a hormonal contraceptive, an intrauterine device, double-barrier method, or abstinence. A woman of childbearing potential is defined as any female who is less than 2 years post-menopausal or has not undergone a partial or total hysterectomy or surgical sterilisation, e.g. bilateral tubal ligation, bilateral oophorectomy.
• Women of childbearing potential who are unwilling to undergo a urine pregnancy test.
• Have an alcohol intake in excess of 14 units per week for females and 21 units per week for males.
• Have a history of drug abuse or positive test results for drug abuse.
• Is a current smoker.
• Have used prescription drugs (not including oral contraceptives) within 14 days prior to study drug administration or have used over-the-counter drugs, herbal products/supplements, or vitamins within 14 days prior to study drug administration, unless the Principal Investigator and Sponsor agree that the product taken will not impact on study conduct, results or participant safety.
• Currently, or in last 30 days, participating in a clinical trial involving another study drug
• Have donated blood or blood products within 30 days prior to study drug administration
• Have a clinically significant abnormal laboratory test (as determined by the Principal Investigator)
• Suffering from any other diseases or condition which, in the opinion of the investigator, means that the participant is unsuitable for the study.
• Have previously undergone nasal surgery or experienced nasal trauma (including broken nose).
• Midazolam Contraindications: Have a hypersensitivity to benzodiazepines, acute narrow angle glaucoma, or myasthenia gravis.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation of the treatment sequence using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
All participants who were randomised into the study and who receive a single dose of the study drug will be included in the safety analysis. Pharmacokinetic parameters will be calculated and compared for all participants that completed both study periods, and have sufficient concentration-time data to estimate PK parameters.

Pharmacokinetic Analysis
On the basis of the concentration-time data, the following pharmacokinetic parameters will be estimated for midazolam from the plasma concentration against time data, using a non-compartmental model:
AUC0-t: The area under the plasma concentration versus time curve from time zero to the last measurable concentration, as calculated by the linear trapezoidal method
AUC0-8: The area under the plasma concentration versus time curve, from zero to infinity. AUC0-8 is calculated as the sum of the AUC0-t plus the ratio of the last measurable concentration to the elimination rate constant (Ct/Kel).
Cmax: Maximum measured plasma concentration directly obtained from the experimental data of plasma concentration versus time curves, without interpolation.
Tmax: Time of maximum measured plasma concentration. If the maximum value occurs at more than one point, Tmax is defined as the time of the first occurrence.
T1/2: Time required for the plasma drug concentration to decrease by one half. This value is estimated from the elimination rate constant (Kel) calculated from the slope of the linear relationship between the loge concentration and time during the terminal elimination phase.
Additionally, the following parameters will be estimated for 1-hydroxymidazolam (1-OH MDZ)
AUC(0-t): The area under the plasma concentration versus time curve from time zero to the last measurable concentration, as calculated by the linear trapezoidal method
AUC(0-8): The area under the plasma concentration versus time curve, from zero to infinity. AUC0-8 is calculated as the sum of the AUC0-t plus the ratio of the last measurable concentration to the elimination rate constant (Ct/Kel).
Cmax: Maximum measured plasma concentration directly obtained from the experimental data of plasma concentration versus time curves, without interpolation.
Plasma concentrations for each treatment at each time and the pharmacokinetic parameters will be summarised by randomised treatment using standard descriptive statistics, including means, medians, geometric means, ranges, inter-quartile ranges, standard deviations and standard errors.
Bioavailability assessments will be performed on loge-transformed AUC0-t, AUC0-8, and Cmax data to obtain geometric means for each treatment. The ratio of the geometric means between the MDZ with NasoSURF group and the MDZ-IV will be calculated. The ANOVA model used in bioavailability assessments will include fixed effects for period and treatment and participant as a random effect. The comparisons between treatments will be summarised as the ratio of the geometric means with 90% confidence intervals.
The additional pharmacokinetic parameter t1/2 will be summarized as mean with 95% confidence interval and compared between the different treatments using ANOVA as described above. Tmax will be summarized as medians with inter-quartile ranges and compared between treatments using Wilcoxon signed rank tests.


Pharmacodynamic Analysis
Mean differences from baseline in OAA/S (composite and sum) scores will be calculated for all treatments at all time points (pre-dose to 8 hours post dose). Using these differences, the following parameters will be calculated:
Peak Effect: The maximum change in OAA/S scores from baseline
Time to Peak Effect: The time to the maximum in OAA/S scores from baseline (minutes)
AUC: The Area Under the Curve of the difference in OAA/S scores from baseline for:
- 0-1 hours
- 0-2 hours
- 0-4 hours
- 0-6 hours
- 0-8 hours
Peak effect, Time to peak effect, and all the AUCs will be summarised using values at each time by randomised treatment using standard descriptive statistics, including means, medians, geometric means, ranges, inter-quartile ranges, standard deviations and standard errors.
Areas under the effect curves for OAA/S (composite, sum) as well as Peak effect and Time to peak effect will be analysed using an ANOVA model which includes fixed effects for period and treatment and participant as a random effect. The comparisons between treatments will be summarised as the ratio of the geometric means with 95% confidence intervals

Safety Analysis
AEs will be collected for all randomised participants and will be listed with type of AE, severity and relationship for each treatment group, using the safety population. Safety data will be summarised for each formulation using frequencies and percentages (% of participants with each specific AE). Known Midazolam specific AEs maybe compared between treatments using McNemar’s chi-square tests when frequencies are sufficient.
The haematology and biochemistry data collected pre-study and after each period will be summarised descriptively using means, medians, standard deviations, ranges and frequencies and percentages as appropriate. Individual values outside normal ranges and considered clinically significant will be individually listed. Comparisons of the haematology and biochemistry measures associated with each treatment may be compared between treatments using repeated measures ANOVA and McNemar’s chi-square tests.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/01/2023
Actual
Date of last participant enrolment
Anticipated
13/02/2023
Actual
Date of last data collection
Anticipated
20/02/2023
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment outside Australia
Country [1] 24033 0
New Zealand
State/province [1] 24033 0

Funding & Sponsors
Funding source category [1] 309373 0
Commercial sector/Industry
Name [1] 309373 0
AFT Pharmaceuticals Ltd
Country [1] 309373 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
AFT Pharmaceuticals Ltd
Address
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland 0622,
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310345 0
None
Name [1] 310345 0
Address [1] 310345 0
Country [1] 310345 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309189 0
Health and Disability Ethics Committee
Ethics committee address [1] 309189 0
Ethics committee country [1] 309189 0
New Zealand
Date submitted for ethics approval [1] 309189 0
30/09/2021
Approval date [1] 309189 0
21/01/2022
Ethics approval number [1] 309189 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113282 0
Dr Alex Cole
Address 113282 0
New Zealand Clinical Research
4/264 Antigua Street
Christchurch 8011
New Zealand
Country 113282 0
New Zealand
Phone 113282 0
+6433729477
Fax 113282 0
Email 113282 0
[email protected]
Contact person for public queries
Name 113283 0
Laura Boddington
Address 113283 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 113283 0
New Zealand
Phone 113283 0
+6494880232
Fax 113283 0
Email 113283 0
[email protected]
Contact person for scientific queries
Name 113284 0
Laura Boddington
Address 113284 0
AFT Pharmaceuticals Ltd.
Level 1, 129 Hurstmere Road,
Takapuna,
Auckland,
New Zealand 0622
Country 113284 0
New Zealand
Phone 113284 0
+6494880232
Fax 113284 0
Email 113284 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.