Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001077257
Ethics application status
Approved
Date submitted
6/06/2018
Date registered
28/06/2018
Date last updated
19/12/2018
Date data sharing statement initially provided
19/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A healthy volunteer study evaluating the the safety, tolerability, and pharmacokinetics of RT234
Scientific title
A Phase I, Two-Part, Single-Center, Open-Label, Randomized, Cross Over, Single Ascending Doses (SAD), followed by a Multiple Ascending Doses (MAD) Safety and Pharmacokinetic Study of RT234 in Healthy Subjects
Secondary ID [1] 294986 0
Protocol number RT234-CL101
Universal Trial Number (UTN)
U1111-1214-5515
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 307998 0
Condition category
Condition code
Respiratory 307027 307027 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
RT234 consists of capsules of a dry powder formulation containing either 0.2 milligram or 0.6 milligram of active substance. Each dose of RT234 is administered via oral inhalation with a non invasive, dry powder inhaler.

This is a Phase 1, two-part, open-label, randomized, cross-over safety and PK study of RT234 in healthy subjects. Part 1 is the Single Ascending Dose (SAD) portion. Part 2 is the Multi-Ascending Dose (MAD) portion.

For Part 1 (SAD) of the study, there are 4 cohorts with 6 participants in each cohort. Participants in each cohort will receive a single dose RT234. Cohort 1 participants will receive a single dose of 200 mcg of RT234. Cohort 2 participants will receive a single dose of 600 mcg of RT234 and a single dose of 20 mg of the oral comparator, vardenafil. Cohort 3 participants will receive a single dose of 1200 mcg of RT234. Cohort 4 participants will receive a single dose of 2400 mcg of RT234.

In Cohort 2 only, one half of of the participants will be randomized to receive a single inhaled dose of RT234 (600 mcg) on Day 1 while the other half will receive a single 20mg oral dose of the comparator. Participants will then cross-over to receive their alternate treatment (RT234 or oral comparator) on Day 3

For Part 2 (MAD) of the study, 8 participants will receive 2 doses of RT234 on the first day, 3 doses of RT234 on the second day, and 4 doses of RT234 for the next 6 consecutive days (one dose of RT234, four times a day, from Day 3 - Day 9) The dose for Part 2 (MAD) will be the highest safe dose as determined in Part 1 (SAD) by the Safety Monitoring Committee. Depending on the results of Part 1 (SAD), participants participating in Part 2 (MAD) could receive up to a total of 9600 mcg/day of RT234 (2400 mcg four times a day)

Each dose administration will be observed by the study site staff to ensure correct technique is being utilised and that the entire dose has been inhaled. The study site staff will also evaluate the used capsule after administration to confirm that no dose remains in the used capsule.

Participation ranges from 7 days to 14 days, depending on which part of the study and which cohort the participant is assigned to.

Participants will only be enrolled in 1 part. Participants in Part 1 cannot participate in Part 2.
Intervention code [1] 301315 0
Treatment: Drugs
Comparator / control treatment
Only Cohort 2 in Part 1 (SAD) portion will have a comparator, 20 mg tablet of vardenafil.
Control group
Active

Outcomes
Primary outcome [1] 306008 0
Safety of 4 dose levels of RT234 in both males and females by assessing the collection of safety data, such as clinical laboratory tests, vital signs, ECGs, spirometry, and physical exams.
Timepoint [1] 306008 0
Clinical laboratory tests will be collected at screening, upon admission into clinic (Day -1), 4 hours post study dose, Day 2 (Part 1 SAD; cohort 2), Day 10 (Part 2 MAD), upon discharge from clinical, and at the follow-up visit.

Vital signs will be measured at screening, upon admission into clinic, pre-dose, 15 minutes, 30 minutes, 45 minutes, 1hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 8 hour, and 12 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

ECGs will be measured at screening, upon admission into clinic, pre-dose, 1 hour, 2 hour, and 4 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

Spirometry will be measured at screening, pre-dose, and 30 minutes post dose.

Physical exams will be taken at screening, upon admission into clinic, 4 hours post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from the clinic, and at the follow up visit.

All participants will be dosed on Day 1 and discharged on Day 2 (Cohorts 1, 3, 4), Day 4 (Cohort 2), and Day 10 (Part 2 MAD). Each participant will also return to clinic for a follow-up visits on Day 6 (Cohort 1, 3, 4), Day 8 (Cohort 2), Day 10 (Part 2 MAD).
Primary outcome [2] 306009 0
Safety of the highest single dose of RT234, repeated up to 4 times daily, for 7 days by assessing the collection of safety data, such as clinical laboratory tests, vital signs, ECGs, spirometry, and physical exams.
Timepoint [2] 306009 0
Clinical laboratory tests will be collected at screening, upon admission into clinic (Day -1), 4 hours post study dose, Day 2 (Part 1 SAD; cohort 2), Day 10 (Part 2 MAD), upon discharge from clinical, and at the follow-up visit.

Vital signs will be measured at screening, upon admission into clinic, pre-dose, 15 minutes, 30 minutes, 45 minutes, 1hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 8 hour, and 12 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

ECGs will be measured at screening, upon admission into clinic, pre-dose, 1 hour, 2 hour, and 4 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

Spirometry will be measured at screening, pre-dose, and 30 minutes post dose.

Physical exams will be taken at screening, upon admission into clinic, 4 hours post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from the clinic, and at the follow up visit.

All participants will be dosed on Day 1 and discharged on Day 2 (Cohorts 1, 3, 4), Day 4 (Cohort 2), and Day 10 (Part 2 MAD). Each participant will also return to clinic for a follow-up visits on Day 6 (Cohort 1, 3, 4), Day 8 (Cohort 2), Day 10 (Part 2 MAD).
Secondary outcome [1] 347291 0
Pharmacokinetic profile and dose linearity with 4 single doses of RT234 by determining the pharmacokinetic parameters (Tmax, Cmax, AUC, and half-life) via blood samples.
Timepoint [1] 347291 0
Blood samples will be taken at pre-dose, immediately post dose at 2, 5, 10, 15, 30, and 45 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 14 hour post dose, upon discharge from the clinic, and at the follow up visit.

All participants will be dosed on Day 1 and discharged on Day 2 (Cohorts 1, 3, 4), Day 4 (Cohort 2), and Day 10 (Part 2 MAD). Each participant will also return to clinic for a follow-up visits on Day 6 (Cohort 1, 3, 4), Day 8 (Cohort 2), Day 10 (Part 2 MAD).
Secondary outcome [2] 347292 0
Pharmacokinetic profiles of the 0.6 milligram capsule of RT234 against a 20 mg oral dose of the comparator in a cross-over manner by determining the pharmacokinetic
parameters (Tmax, Cmax, AUC, and half-life) via blood samples
Timepoint [2] 347292 0
Blood samples will be taken at pre-dose, immediately post dose at 2, 5, 10, 15, 30, and 45 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 14 hour post dose, upon discharge from the clinic, and at the follow up visit.

All participants will be dosed on Day 1 and discharged on Day 2 (Cohorts 1, 3, 4), Day 4 (Cohort 2), and Day 10 (Part 2 MAD). Each participant will also return to clinic for a follow-up visits on Day 6 (Cohort 1, 3, 4), Day 8 (Cohort 2), Day 10 (Part 2 MAD).
Secondary outcome [3] 347293 0
Demonstrate a safe high dose that can be moved forward into the MAD portion (Part 2) of the study by assessing the collection of safety data, such as clinical laboratory tests, vital signs, ECGs, spirometry, and physical exams.
Timepoint [3] 347293 0
Clinical laboratory tests will be collected at screening, upon admission into clinic (Day -1), 4 hours post study dose, Day 2 (Part 1 SAD; cohort 2), Day 10 (Part 2 MAD), upon discharge from clinical, and at the follow-up visit.

Vital signs will be measured at screening, upon admission into clinic, pre-dose, 15 minutes, 30 minutes, 45 minutes, 1hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 8 hour, and 12 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

ECGs will be measured at screening, upon admission into clinic, pre-dose, 1 hour, 2 hour, and 4 hour post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from clinic, and at the follow up visit.

Spirometry will be measured at screening, pre-dose, and 30 minutes post dose.

Physical exams will be taken at screening, upon admission into clinic, 4 hours post dose, Day 2 (Part 1 SAD cohort 2), upon discharge from the clinic, and at the follow up visit.

All participants will be dosed on Day 1 and discharged on Day 2 (Cohorts 1, 3, 4), Day 4 (Cohort 2), and Day 10 (Part 2 MAD). Each participant will also return to clinic for a follow-up visits on Day 6 (Cohort 1, 3, 4), Day 8 (Cohort 2), Day 10 (Part 2 MAD).

Eligibility
Key inclusion criteria
1. Healthy male or female, 18 to 45 years of age (inclusive at time of informed consent)
2. Willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures
3. Normal heart, lung, kidney, and liver function based on physical examination
4. Systolic blood pressure of 100-145 mmHg, diastolic blood pressure of 50-90 mmHg, and a resting heart rate of 40-100 beats per minute at Screening
5. Body mass index within the range of 18.0 to 32.0 inclusive at Screening
6. Must be a non-smoker or ex-smoker with less than a 5-pack year history of smoking (including the use of electronic cigarettes) and have ceased smoking over 1 year prior to Screening; or a social smoker (defined as less than 10 cigarettes in the previous 12 months)
7. Females must be non-pregnant and non-lactating, and either surgically sterile or use highly effective contraceptive method from Screening until study completion, including the follow-up period, or be post menopausal for more than 12 months. Postmenopausal status will be confirmed through testing of follicle stimulating hormone (FSH) levels . Females who are abstinent from heterosexual intercourse will also be eligible.

Males must be surgically sterile (more than 30 days since vasectomy with no viable sperm), abstinent, or if engaged in sexual relations with a woman of child-bearing potential, the participant and his partner must be surgically sterile or using an acceptable, highly effective contraceptive method from Screening until study completion, including the follow-up period.

Subjects with same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their preferred and usual lifestyle.

Women of child-bearing potential must have a negative pregnancy test at Screening and Day 1 and be willing to have additional pregnancy tests as required throughout the study
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the follow-up period
2. Known hypersensitivity to active drug substance or drugs of the same class, or any excipients of the drug formulation(s)
3. History or clinical evidence of any disease and or medical condition which may interfere with the absorption, distribution, metabolism, or excretion of the study treatment
4. Has serum transaminase levels greater than three times the upper level of normal
5. Abnormal orthostatic vital signs (at screening) defined as a decrease of greater than or equal to 20 mmHg in systolic blood pressure and or a decrease of greater than or equal to 10 mmHG in gystolic blood pressure and or greater than 25 beats per minute increase in heart rate within 3 minutes of standing, or with symptoms of lightheadedness, dizziness, or fainting upon standing.
6. History of hypotension including fainting, syncope, orthostatic hypotension, and or vasovagal reactions
7. History of cardiopulmonary diseases (cardiovascular, pulmonary, and pleural disorders) and/or cardiopulmonary symptoms of breathlessness, cough and or wheezing
8. History of drug abuse
9. History of alcohol abuse (defined as more than 12 standard drinks per week), consumption food or drink containing grapefruit or seville orange within 72 hours before start of dosing or expected to do so through end of study/early termination
10. Use of any prescription drugs (other than hormonal contraception; OCP’s, long-acting implantable hormones, injectable hormones, a vaginal ring or an IUD), non-prescription drugs, herbal remedies, supplements or vitamins 2 weeks prior to dosing and during course of study without prior approval of the Investigator and Medical Monitor.
11. History of retinitis pigmentosa
12. Vision loss due to non-arteritic anterior ischemic optic neuropathy or other optic perfusion impairment
13. History of priapism or anatomical deformation of the penis
14. History of sudden sensorineural hearing loss (SSHL), need for hearing aids, and or other documented hearing loss
15. A corrected QT interval using Fridericia’s formula (QTcF) greater than 450 msec
16. Has evidence of significant obstructive lung disease on spirometry. Subjects with any of the following criteria will be excluded:
a. Forced expiratory volume in 1 second (FEV1 ) less than 60% (predicted) (pre bronchodilators); or
b. Forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC) less than 65% (pre-bronchodilators)
17. Use of any IP or investigational medical device within 30 days prior to Screening, or 5 half-lives of the product (whichever is the longest) or participation in more than four investigational drug studies within 1 year prior to Screening
18. Presence or history of any condition that, in the view of the Investigator, may affect full participation or compliance with the protocol, or would affect safety

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed; open-label study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
2 Part study
Part 1 is a single ascending dose study with 4 cohorts. The second cohort will be a cross over cohort.
Part 2 is a multi-ascending dose study with 1 cohort.

Decisions to escalate, expand or decrease the dose for both the SAD and MAD portions of the study will be dependent upon review of emerging safety data by a Safety Monitoring Committee (SMC). The SMC will conduct a review of the safety and PK data from Cohort 2 which will determine the dose ranges for the subsequent Part 1 (SAD) cohorts
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Descriptive statistics (for example, arithmetic mean, standard deviation, median, minimum and maximum) will be calculated for continuous safety data among treatment groups (or sequences), by study part, and protocol specified time-point, while frequency summary (for example, number of observed and percentage of each categories) will be applied for categorical safety data among treatment groups (or sequences), by study part, and protocol specified time-point.

No formal hypothesis testing will be performed for this study.

The Safety Population will comprise all subjects who received any amount of study drug. The Safety Population will be used for all data listings and the summaries of all safety assessments.

The Pharmacokinetic population will comprise all subjects who received any amount of study drug, have sufficient plasma concentration-time data to determine at least one PK parameter. The Pharmacokinetic population will be used for the summaries of all PK data.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/07/2018
Actual
30/07/2018
Date of last participant enrolment
Anticipated
11/09/2018
Actual
8/10/2018
Date of last data collection
Anticipated
24/09/2018
Actual
17/10/2018
Sample size
Target
32
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10978 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 22767 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 299572 0
Commercial sector/Industry
Name [1] 299572 0
Respira Therapeutics Inc.
Country [1] 299572 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
Level 4, 88 Jephson Street
Toowong, Queensland 4066
Country
Australia
Secondary sponsor category [1] 298883 0
Commercial sector/Industry
Name [1] 298883 0
Respira Therapeutics Australia Pty Ltd
Address [1] 298883 0
C/- HLB Mann Judd
Level 15, Central Plaza Two
66 Eagle Street
Brisbane, Queensland 4000
Country [1] 298883 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300471 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 300471 0
Ethics committee country [1] 300471 0
Australia
Date submitted for ethics approval [1] 300471 0
25/05/2018
Approval date [1] 300471 0
24/07/2018
Ethics approval number [1] 300471 0
320/18

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

Contacts
Principal investigator
Name 83766 0
Dr Ben Synder
Address 83766 0
Nucleus Network
Level 5, Burnet Institute
AMREP Precinct
89 Commercial Road
Prahan, Victoria 3004
Country 83766 0
Australia
Phone 83766 0
+61 3 8593 9838
Fax 83766 0
Email 83766 0
[email protected]
Contact person for public queries
Name 83767 0
Mari Maurer
Address 83767 0
Respira Therapeutics Inc.
155 Bovet Road
No. 303
San Mateo, CA 94402
Country 83767 0
United States of America
Phone 83767 0
+1 415 827 6713
Fax 83767 0
Email 83767 0
[email protected]
Contact person for scientific queries
Name 83768 0
Mari Maurer
Address 83768 0
Respira Therapeutics Inc.
155 Bovet Road
No. 303
San Mateo, CA 94402
Country 83768 0
United States of America
Phone 83768 0
+1 415 827 6713
Fax 83768 0
Email 83768 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
It's a healthy volunteer study and the individual participant data will not be valuable to the participants or to others outside of the sponsor.


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
SourceTitleYear of PublicationDOI
EmbaseSafety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- And Multiple-Dose Study in Healthy Subjects.2021https://dx.doi.org/10.1089/jamp.2020.1651
N.B. These documents automatically identified may not have been verified by the study sponsor.