Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001702808
Ethics application status
Approved
Date submitted
16/11/2021
Date registered
13/12/2021
Date last updated
3/05/2023
Date data sharing statement initially provided
13/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study of Clofazimine Inhalation Suspension (MNKD-101) in Healthy Volunteers
Scientific title
A Phase 1, Randomized, Double-Blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Clofazimine Inhalation Suspension (MNKD-101) in Healthy Volunteers
Secondary ID [1] 305622 0
MKC-CI-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Nontuberculous Mycobacteria Infections 324053 0
Condition category
Condition code
Infection 321566 321566 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
MNKD-101 is an inhalation suspension of clofazimine (CFZ) for the treatment of infections with pulmonary nontuberculous mycobacteria (NTM) both with and without cystic fibrosis.
The study consists of 2 parts.
Part A (Single Ascending Dose): The study will investigate the safety, tolerability, and pharmacokinetics of MNKD-101.
The participants will be allocated in a randomized and double-blind manner at a ratio of 3:1 to receive MNKD-101 or placebo inhalation (6 MNKD-10 :2 placebo)
In total 3 cohorts will be investigated and the dose level for each cohort may be changed based on available data and following Safety Monitoring Committee review. The maximum increment will be 30 mg CFZ (1.5ml MNKD-101) nominal per dose step and the maximal dose will be of 90 mg CFZ (4.5ml MNKD-101) nominal fill dose.
Cohort A1: 30 mg CFZ (1.5ml MNKD-101) single inhaled dose using a nebulizer on Day 1
Cohort A2: 60 mg CFZ (3.0ml MNKD-101) single inhaled dose using a nebulizer on Day 1
Cohort A3: 90 mg CFZ (4.5ml MNKD-101) single inhaled dose using a nebulizer on Day 1
Each cohort consist of distinct group of participants
Part B (Multiple Ascending Dose): The study will investigate the safety, tolerability, and pharmacokinetics of MNKD-101.
In total 2 cohorts will be investigated and the participants will be randomized in a double-blind manner in a 3:1 ratio to receive daily doses of active or placebo treatment for 1 week
Cohort B1: 30 mg CFZ (1.5ml MNKD-101) inhaled multiple ascending daily doses using a nebulizer at the same time each day from Day 1 to Day 7
Cohort B2: The inhaled multiple ascending daily doses administered using a nebulizer to be in Cohort B2 will be determined based on safety and pharmacokinetic data from Part A and Cohort B1
Each cohort consist of distinct group of participants
Part B will commence after the completion of Part A of the study. The decision to commence Cohort B2 and the dose to be administered will be determined by the Safety Monitoring Committee following review of all available safety and pharmacokinetics data from Part A (SAD) and the 7-day safety and pharmacokinetic data from Cohort B1.

Each inhalation will be closely monitored by an unblinded member of the study team, to ensure proper inhalation. Therefore, adherence monitoring for Part A and B is done by the study nurse observing the inhalation.
Intervention code [1] 322024 0
Treatment: Drugs
Comparator / control treatment
The placebo will comprise isotonic saline (0.9% w/v sodium chloride).
Mode of administration: Inhaled dose using a nebulizer
Control group
Placebo

Outcomes
Primary outcome [1] 329328 0
Part A/Part B: To evaluate the safety and tolerability of single and multiple ascending doses of MNKD 101 in healthy adult participants
To be assessed by monitoring
• Incidence, frequency, severity, and duration of treatment-emergent adverse events (TEAEs)
• Incidence, frequency, severity, and duration of serious adverse events (SAEs)
• Vital signs (heart rate, blood pressure, respiratory rate and tympanic temperature)
• Clinical laboratory tests (hematology, coagulation, biochemistry, urinalysis)
• Columbia Suicide Severity Rating Scale (C-SSRS)
• Physical examination (including evaluation of signs of systemic CFZ deposition),
Timepoint [1] 329328 0
Part A: The TEAEs and SAEs are monitored at each intervention timepoint, vital signs continuously monitored from Baseline to Day 43 post dose
Part B: The TEAEs and SAEs are monitored at each intervention timepoint, vital signs continuously monitored from Baseline to Day 57 post dose
Secondary outcome [1] 402153 0
Part A/ Part B: To evaluate the plasma pharmacokinetics (PK) of MNKD-101 following single and multiple ascending doses in healthy adult participants
The following parameters are used to evaluate the pharmacokinetics
• Maximum plasma MNKD-101 concentration (Cmax)
• Time to maximum concentration (Tmax)
• Terminal elimination half-life (t1/2)
• AUC from time zero (from the start of inhalation time) to the last measurable concentration (AUC0-t)
• AUC from time zero (from the start of inhalation time) to 24 hours post dose (AUC0 24 hours)


Timepoint [1] 402153 0
Part A: Blood samples for pharmacokinetics assessment will be collected at predose, and 5, 10, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 12 hours postdose on Day 1, 24 hours postdose (Day 2), 48 hours postdose (Day 3), and on Days 3, 4, 5, and 8
Part B: Blood samples for pharmacokinetics assessment will be collected at predose, and 5, 10, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 12 hours postdose on Day 1, predose on Day 2, Day 3, Day 4, Day 5, and Day 6, predose, and 5, 10, 15, and 30 minutes, and 1, 2, 4, 6, 8, and 12 hours postdose on Day 7, Days 8, Day 15, and Day 36 at approximately the same time as the time of dosing during the treatment period
Secondary outcome [2] 402154 0
Part B: To determine levels of clofazimine (CFZ) in the lung in a subset of participants by performing bronchoalveolar lavage (BAL)
The half of Part B participants will be randomly selected



Timepoint [2] 402154 0
Part B: Bronchoalveolar lavage samples will be collected 6 hours postdose on Days 2, 4, and 7 from MNKD-101-treated participants in Cohort B2 to determine lung levels of CFZ
Secondary outcome [3] 402155 0
Part A/ Part B: To evaluate signs of systemic Clofazimine (CFZ) deposition (blinded observation of skin, sclera, and mouth)
Timepoint [3] 402155 0
Part A: Once daily from Baseline to Day 43 post dose
Part B: Once daily from Baseline to Day 57 post dose

Eligibility
Key inclusion criteria
1. Body Mass Index (BMI) between 18.0 and 32.0 kg/m2 (inclusive). Body weight must be greater than 50 kg.
2. Participants whose smoking habit in the 12 months prior to Screening included no more than 2 cigarettes or equivalent dose per week (includes e-cigarettes and other nicotine and tobacco products) can be included in the study but must be willing to abstain from smoking for one month prior to admission to the Clinical research unit (CRU) and while resident at the CRU. Thorough documentation of smoking habits is required.
3. Negative test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), and Human Immunodeficiency Virus (HIV) antibody at Screening.
4. Female participants must be of non-childbearing potential, as follows:
a. At least 1 year postmenopausal (amenorrhea more than 12 months in the absence of an alternative medical cause and Follicle-stimulating hormone (FSH) greater than 40 IU/mL in women not using hormonal contraception or hormonal replacement therapy) prior to Screening.
b. Surgically sterile (bilateral oophorectomy, hysterectomy, bilateral salpingectomy, or bilateral tubal ligation).
5. To protect partners from possible exposure to study medication in semen, male participants must use a condom during the study, even if they have had a vasectomy or their partner is not of childbearing potential. Males will be required to continue to use condoms for 90 days after the last dose of MNKD-101.
If engaged in sexual relations with a woman of childbearing potential (WOCBP), his partner must be surgically sterile (eg, tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective contraceptive method from Screening until at least 135 days have passed since IP administration. Note: medically acceptable methods of contraception that may be used by the partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, and etonogestrel implant.
Males must not donate sperm for at least 135 days after the last dose of MNKD-101.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically relevant abnormal history, physical findings, Electrocardiogram (ECG), or clinical laboratory values at the Screening assessment or Day 1 that could interfere with the objectives of the study or the safety of the participant.
2. Presence or history of acute or chronic illness sufficient to invalidate the participant’s participation in the study or make it unnecessarily hazardous.
3. A condition that, in the opinion of the Investigator, could compromise the wellbeing of the participant or course of the study, or prevent the participant from meeting or performing any study requirements.
4. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, cancer, or history of any psychotic mental illness.
5. A score on the Columbia Suicide Severity Rating Scale (C-SSRS) consistent with suicidal ideation or behavior.
6. History of asthma, with the exception of resolved childhood asthma.

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/01/2022
Actual
27/01/2022
Date of last participant enrolment
Anticipated
25/03/2022
Actual
19/06/2022
Date of last data collection
Anticipated
13/05/2022
Actual
19/07/2022
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 20951 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 35768 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 309984 0
Commercial sector/Industry
Name [1] 309984 0
MannKind Corporation
Country [1] 309984 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
MannKind Corporation
Address
30930 Russell Ranch Road, Suite 300
Westlake Village, CA 91362 USA
Country
United States of America
Secondary sponsor category [1] 311033 0
None
Name [1] 311033 0
Address [1] 311033 0
Country [1] 311033 0
Other collaborator category [1] 282036 0
Commercial sector/Industry
Name [1] 282036 0
Novotech (Australia) Pty Limited
Address [1] 282036 0
Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country [1] 282036 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309693 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 309693 0
Ethics committee country [1] 309693 0
Australia
Date submitted for ethics approval [1] 309693 0
03/11/2021
Approval date [1] 309693 0
13/12/2021
Ethics approval number [1] 309693 0
HREC/80003/Alfred-2021

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

Contacts
Principal investigator
Name 115062 0
Dr Paul Griffin
Address 115062 0
Q-Pharm Pty Ltd
Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006
Country 115062 0
Australia
Phone 115062 0
+61 7 3707 2700
Fax 115062 0
Email 115062 0
[email protected]
Contact person for public queries
Name 115063 0
Paul Griffin
Address 115063 0
Q-Pharm Pty Ltd,
Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006
Country 115063 0
Australia
Phone 115063 0
+61 7 3707 2700
Fax 115063 0
Email 115063 0
[email protected]
Contact person for scientific queries
Name 115064 0
Thomas Hofmann
Address 115064 0
MannKind Corporation
One Casper Street
Danbury, CT 06810
USA
Country 115064 0
United States of America
Phone 115064 0
+1 267 884 3042
Fax 115064 0
Email 115064 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.