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Trial registered on ANZCTR


Registration number
ACTRN12622001077752p
Ethics application status
Submitted, not yet approved
Date submitted
10/06/2022
Date registered
4/08/2022
Date last updated
4/08/2022
Date data sharing statement initially provided
4/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Pharmacokinetic and Safety Comparison of Oxytocin Administered as a Dry Powder by Inhalation and by Intravenous and Intramuscular Injection in Healthy Female Participants
Scientific title
A Randomized, Single-Center, Partially Single-Blind Study to Investigate the Pharmacokinetics, Safety, and Tolerability of Single and Repeated Doses of Oxytocin Administered via Inhalation or Intravenous or Intramuscular Administration in Healthy Female Participants
Secondary ID [1] 307294 0
642889PPH1001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postpartum Haemorrhage 326579 0
Condition category
Condition code
Reproductive Health and Childbirth 323824 323824 0 0
Normal pregnancy
Reproductive Health and Childbirth 324078 324078 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All subjects to complete all dosing sessions.
Dosing Session 1 (DS1) (to be completed on 4 consecutive days, all subjects receive all 4 treatments in a randomised order):
Oxytocin dry powder inhaler 150mcg single dose
Oxytocin dry powder inhaler placebo single dose
Oxytocin 10IU intramuscular injection - Comparator - Single dose
Oxytocin 5IU intravenous injection (administered over 5 mins) - Comparator - Single dose

Dosing Session 2 (DS2) (to be completed as soon as possible on completion of DS1 with a minimum of 24hrs between dosing sessions):
Each subject to be randomised to receive one of the following:
Oxytocin dry powder inhaler 600mcg single dose (14 Subjects)
Oxytocin dry powder inhaler placebo single dose (2 Subjects)

Dosing Session 3 (DS3) (to be completed 12 weeks after DS2, subjects to be randomised to placebo or active):
Oxytocin dry powder inhaler 900mcg single dose (administered as 3x300mcg doses with no interval between doses) - 7 subjects
Oxytocin dry powder inhaler placebo single dose (administered as 3x single placebo dose with no interval between doses) - 1 subject
Oxytocin dry powder inhaler 300mcg (three doses administered at 10 minute intervals for a total dose of 900mcg) - 7 Subjects
Oxytocin dry powder inhaler placebo (three doses administered at 10 minute intervals) - 1 subject.

All interventions will be administered under close clinical supervision at the clinical pharmacology unit. Dosing session 1 will be completed with subjects remaining in the unit on an inpatient basis. Placebo dry powder inhaler comprises trehalose, leucine and calcium chloride and is identical to the active dry powder inhaler with the exception that the active component is replaced by trehalose.
Intervention code [1] 323739 0
Prevention
Intervention code [2] 323740 0
Treatment: Drugs
Comparator / control treatment
The comparator treatment will be an oxytocin 10IU intramuscular injection administered as a 1mL bolus dose
Control group
Active

Outcomes
Primary outcome [1] 331613 0
Pharmacokinetic sampling of blood to be assessed for oxytocin content using a specific and sensitive validated LC-MSMS bioanalytical assay.
Parameters to be assessed:
Cmax - Maximum observed plasma oxytocin concentration
Cp(10min) - Quantified plasma oxytocin concentration at 10 minutes (nominal time) postdose
Cp(20min) - Quantified plasma oxytocin concentration at 20 minutes (nominal time) postdose
Cp(30min) - Quantified plasma oxytocin concentration at 30 minutes (nominal time) postdose
Clast - Last observed measurable (non-below quantification limit [non-BQL]) plasma oxytocin concentration
Tmax - Time to reach the maximum observed plasma oxytocin concentration
Tlast - Time to reach the last observed measurable (non-BQL) plasma oxytocin concentration
AUC(0-t) - Area under the plasma oxytocin concentration- time curve (AUC) from time 0 to t time postdose
AUClast - Area under the plasma oxytocin concentration vs time curve from time 0 to time of the last measurable (non-BQL) concentration.
AUCinf - Area under the plasma oxytocin concentration vs. time curve from time 0 to infinite time.
AUC(0-10 min) - Area under the plasma oxytocin concentration- time curve (AUC) from time 0 to 10 minutes postdose
AUC(0-20 min) - Area under the plasma oxytocin concentration- time curve (AUC) from time 0 to 20 minutes postdose
AUC(0-30 min) - Area under the plasma oxytocin concentration- time curve (AUC) from time 0 to 30 minutes postdose
AUC(0-3h) - Area under the plasma oxytocin concentration- time curve (AUC) from time 0 to 3 hours postdose
AUCex - Extrapolated AUC, calculated as Ct/lambda-z
t1/2 - Apparent elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve
lambda-z - Apparent terminal elimination rate constant, estimated by linear regression using the terminal log-linear phase of the log transformed concentration-time curve
Timepoint [1] 331613 0
Pre-dose, +2 mins, +3 mins,+5 mins, +10 mins, +20min, +0.5h, +0.75h, +1h, +1.5h, +2h, +2.5h, +3h, +4h, +6h after completion of dose administration
Secondary outcome [1] 410549 0
Safety and tolerability as determined by vital signs, electrocardiogram (ECG), clinical safety laboratory assessments and spirometry

Temperature (tympanic), pulse/heart rate, respiratory rate, saturation of peripheral oxygen (SpO2), and blood pressure will be assessed.

Blood pressure and pulse/heart rate measurements will be assessed with a completely automated device consisting of an inflatable cuff and an oscillatory detection system. Blood pressure and pulse/heart rate measurements will be recorded after 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones) in a supine position.

SpO2 measurement will be assessed with a pulse oximeter. SpO2 measurement will be recorded as a single reading after 5 minutes of rest in a quiet setting in a supine position.

Clincal safety lab assessments: Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will be collected. Adverse respiratory events will be monitored by spirometry. The spirometry test will be performed in each period or Dosing Session with inhaled oxytocin or inhaled placebo administration. The forced expiratory volume (FEV1.0) and forced vital capacity (FVC) will be performed in triplicate at each time point i.e. the subject should provide three acceptable measurements at each timepoint.

Physical examinations including height and body weight
A full physical examination will include assessments of the following: head, eyes, ears, nose, throat (HEENT), neck, chest, lungs, abdomen, musculoskeletal, dermatological, cardiovascular/peripheral vascular, and general neurological examination.
A brief physical examination will include assessments of the following: HEENT, chest, lungs, abdomen, dermatological, cardiovascular/peripheral vascular, and areas of note elicited from the participant.
Timepoint [1] 410549 0
Full physical examination will be conducted at screening and Day -1 prior to each dosing session. A brief physical examination will be conducted immediately pre-dose in Dosing Session 1.
Vital signs - +10min, +1hr, +2hr, +6hr after completion of dose administration & follow up
Clinical laboratory assessments - Pre-dose, +6hrs after completion of dose administration & follow up
Spriometry - +10min, +0.5hr, +1hr, +6hr after completion of dose administration & follow up

Follow-up will be conducted as a single visit 7-21 days after final dosing

Eligibility
Key inclusion criteria
1. Premenopausal women 18 to 45 years of age, inclusive.
2. Healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening and at admission to the study center.
3. Healthy on the basis of clinical laboratory tests performed at screening and at admission to the study center.
4. Must be physically capable of using an oral inhalation dry-powder-inhaler device without physical assistance.
5. Must have FEV1.0 within normal range at screening and before the start of administration of each treatment.
6. Body weight not less than 45 kg and body mass index (BMI; weight kg/m2) within the range of 18 – 30 kg/m2 (inclusive).
7. Premenopausal woman:
All women must be of childbearing potential
8. All women must have a negative highly sensitive serum (human chorionic gonadotropin [hCG]) at screening and a negative urine pregnancy test on Day -1 (or on Day 1) of Dosing Session 1 and must not be lactating.
9. All women must be using two methods of contraception, including a combined estrogen-containing OCP for a 30-day minimum period before screening, and must be willing to continue using two methods of contraception, including their current OCP schedule, for the duration of the study and until completion of the follow-up visit.
10. A woman must agree not to donate eggs (ova, oocytes), or freeze for future use, for the purposes of assisted reproduction during the study and for a period of at least 30 days after the last dosing day.
11. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Other Inclusions
12. Blood pressure (after the participant is supine for 5 minutes) between 90 and 140 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of or current clinically significant medical illness
2. Chronic lung condition of any aetiology including adult asthma, chronic obstructive pulmonary disease (COPD), emphysema, bronchospastic respiratory disease and interstitial lung diseases.
3. Underlying cardiovascular diseases (including hypertrophic cardiomyopathy, valvular heart disease, and/or ischemic heart disease including coronary artery vasospasm).
4. Previous or current clinical history of proven pulmonary or systemic tuberculosis.
5. Proven or suspected respiratory tract infection / pneumonia of any aetiology within 4 weeks of screening.
6. History of pulmonary embolus, pulmonary hypertension of any aetiology, and peripheral venous thromboembolism.
7. Use of an intrauterine device (IUD) within last 3 months prior to screening.
8. Any pregnancy within the last 12 months prior to screening.
9. Gynecological disorders or other diseases which can increase the risk of pelvic fibrosis.
10. Alanine transaminase (ALT) [or aspartate transaminase (AST)] >1.5 x upper limit of normal (ULN).
11. Total bilirubin >1.5 x ULN (isolated total bilirubin >1.5 x ULN is allowed for those participants with known Gilbert’s syndrome; Gilbert’s syndrome is suggested by direct bilirubin <30%).
12. Current or chronic history of liver disease.
13. Known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
14. Known allergies, hypersensitivity, or intolerance to IH oxytocin or oxytocin injection, or their excipients.
15. History of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation such as – allergy to latex; allergy to any previous inhaler use.
16. Contraindications to the use of oxytocin injection per local prescribing information
17. Taken any disallowed therapies before the planned first dose of study intervention.
18. Received an investigational intervention, including investigational vaccines, or used an invasive investigational medical device within 1 month or within a period less than 5 times the drug’s half-life, if known, whichever is longer, before the planned first dose of study intervention, or received an investigational biological product within 3 months or 5 half-lives, whichever is longer, before the planned study intervention. In case the half-life of the biological product is not known, the exclusion window will be 6 months before the first dosing day.
19. Is currently enrolled in an investigational study.
20. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
21. Had major surgery, (eg, requiring general anesthesia) within 3 months before screening (if fully resolved with no further follow up required), or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study or within 60 days after the last dose of study intervention administration.
22. Current human immunodeficiency virus type 1 (HIV-1) or HIV-2 infection (confirmed by antibodies) at screening.
23. Presence of hepatitis B surface antigen (HBsAg) [or hepatitis B core antibody (HBcAb)] at screening or within 3 months prior to first dose of study intervention.
24. Positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention.
25. History of hepatitis A within 3 months prior to screening or current hepatitis A infection (confirmed by hepatitis A antibody immunoglobulin M [IgM]).
26. Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
27. History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 3 years before screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opioids, cocaine, cannabinoids, amphetamines, hallucinogens such as Phencyclidine (PCP), and benzodiazepines) at screening.
28. A positive urine drug test and/or alcohol test may be repeated once (as soon as possible and within the screening period) to exclude a technical error. Participants with a negative urine drug and/or alcohol test at retest may be included.
29. Known allergy to heparin or history of heparin induced thrombocytopenia.
30. Donated blood or blood products or had substantial loss of blood (more than 500 mL) within 3 months before the first administration of study drug or intention to donate blood or blood products during the study.
31. Must not have used nicotine-containing substances including tobacco products (eg, cigarettes, e-cigarettes, cigars, chewing tobacco, gum, or patch) for at least 1 month prior to screening and not more than one cigarette per week for 3 months prior to screening.
32. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 8 weeks after the last dose of study intervention.
33. Vulnerable participant (eg, incarcerated individual).
34. Lack of good/reasonable venous access.
35. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

Study design
Purpose of the study
Prevention
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
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2022
Actual
Date of last participant enrolment
Anticipated
30/09/2022
Actual
Date of last data collection
Anticipated
30/01/2023
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 311586 0
Commercial sector/Industry
Name [1] 311586 0
Janssen Biotech, Inc
Country [1] 311586 0
United States of America
Funding source category [2] 311588 0
Government body
Name [2] 311588 0
Victorian State Government
Country [2] 311588 0
Australia
Funding source category [3] 311589 0
Government body
Name [3] 311589 0
Australian Federal Government
Country [3] 311589 0
Australia
Primary sponsor type
University
Name
Monash University
Address
381 Royal Parade, Parkville, Victoria, 3052
Country
Australia
Secondary sponsor category [1] 313026 0
None
Name [1] 313026 0
Address [1] 313026 0
Country [1] 313026 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311036 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 311036 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 311036 0
Australia
Date submitted for ethics approval [1] 311036 0
27/06/2022
Approval date [1] 311036 0
Ethics approval number [1] 311036 0

Summary
Brief summary
To evaluate the pharmacokinetics, safety and tolerability of a novel dry powder oxytocin inhaler in comparison to oxytocin intravenous and intramuscular injections.

To assess and quantify how effectively oxytocin can be delivered into the human blood stream as a powder from an inhalation device compared with delivery via an intravenous or intramuscular injection. In addition to assess if oxytocin can be delivered as a powder from an inhalation device without causing adverse effects to the recipient
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119770 0
Dr Sam Francis
Address 119770 0
Nucleus Network, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 119770 0
Australia
Phone 119770 0
+61 03 8593 9800
Fax 119770 0
Email 119770 0
s.francis@nucleusnetwork.com.au
Contact person for public queries
Name 119771 0
Dr Nucleus Network Melbourne
Address 119771 0
Nucleus Network Melbourne, Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 119771 0
Australia
Phone 119771 0
+61 1800 243 733
Fax 119771 0
Email 119771 0
melbourne@nucleusnetwork.com
Contact person for scientific queries
Name 119772 0
Mr Peter Lambert
Address 119772 0
Monash University, 381 Royal Parade, Parkville, Victoria, 3052
Country 119772 0
Australia
Phone 119772 0
+61 3 99039146
Fax 119772 0
Email 119772 0
pete.lambert@monash.edu

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.