Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000609651
Ethics application status
Approved
Date submitted
29/05/2023
Date registered
2/06/2023
Date last updated
23/06/2024
Date data sharing statement initially provided
2/06/2023
Date results information initially provided
23/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to examine the comparative exposure of N-Acetyl-D-Mannosamine Monohydrate (ManNAc) when administered orally as a solution and two novel tablet formulations in healthy adult males
Scientific title
An open-label, randomised, three-arm crossover study to examine the comparative pharmacokinetics of ManNAc administered as an oral solution and as two novel oral tablet formulations in healthy adult males
Secondary ID [1] 309677 0
ManNAc.03
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
GNE Myopathy 330036 0
Hereditary Inclusion Body Myopathy 330239 0
Condition category
Condition code
Musculoskeletal 326944 326944 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational Product
N-acetyl-D-mannosamine (ManNAc)

Study Treatments
Treatment A: 1000 mg ManNAc oral solution, administered as a single oral dose (1000 mg in 200 mL water).

Treatment B: 990 mg ManNAc chewable tablets, administered as a split oral dose (1 x 330 mg tablet every hour).

Treatment C: 1000 mg ManNAc gastroretentive tablets, administered as a single oral dose (4 x 250 mg tablets).

Treatment will be administered under fasting conditions according to a open-label, randomised, three-arm, crossover design. An Investigator will supervise self-administration of ManNAc treatments by study participants. Each study period will be separated by a washout period of at least 7 days between treatment administrations.
Intervention code [1] 326121 0
Treatment: Drugs
Comparator / control treatment
ManNAc administered via the oral route in the form of a solution (Treatment A) is the comparator.
Control group
Active

Outcomes
Primary outcome [1] 334784 0
ManNAc pharmacokinetic parameters including:
- Area under the concentration versus time profile from 0 to the last quantifiable concentration (AUClast)
- Maximum observed plasma concentration (Cmax)
- Time to maximum plasma concentration (Tmax)
In addition, where the terminal phase of the concentration-time profile can be determined, the following pharmacokinetic parameters will also be calculated:
- Terminal rate constant
- Area under the concentration versus time profile extrapolated to infinite time (AUCinf)
- Terminal half-life (T1/2)
- Clearance (CL)
- Volume of distribution (Vd)

Pharmacokinetic analysis will be based on baseline-corrected plasma ManNAc concentrations,
Timepoint [1] 334784 0
Prior to dosing (0 h) and then at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12 and 24 h.
Secondary outcome [1] 422074 0
Safety parameters including adverse events, vital signs and clinical laboratory tests (haematology and biochemistry)
Timepoint [1] 422074 0
Adverse events will be monitored continuously from Screening until Follow-up (5-7 days after receiving the last study treatment in Study Period 3). As a consistent method to prompt reporting of adverse events, participants will be asked a non-leading question prior to dosing and then at the 4, 12 and 24 h timepoints in each study period. Adverse events will also be solicited during the follow-up phone call.

Vital signs, including blood pressure, pulse rate, respiratory rate, body temperature and pulse oximetry, will be recorded at Screening as well as prior to dosing and then at the 4 h, 12 h and 24 h timepoints in each study period. Study staff will record all vital sign measurements. Specifically, blood pressure and pulse rate will be measured using a sphygmomanometer, body temperature will be measured using a forehead thermometer, respiratory rate will be measured by manual count and oxygen saturation will be measured using a pulse oximeter.

Blood samples collected for clinical laboratory testing (haematology and biochemistry) will be assessed at screening and after completion of the study procedures in Period 3 (i.e. 24 h post final study dose).

Eligibility
Key inclusion criteria
1. Male and aged 18-59 years, inclusive.
2. Body mass index (BMI) is between 18.0 – 30.0 kg/m^2 with a body weight between 45.0 – 120.0 kg.
3. Medically healthy without any clinically significant abnormalities. Health status will be determined by the participant's medical history with specific attention to: (i) drug history, identifying any known drug allergies or drug abuse, (ii) any chronic use of medication, and (iii) a thorough review of body systems (vital signs, electrocardiogram (ECG), physical examination and clinical laboratory tests).
4. Adequate venous access on their left or right arm to allow for collection of multiple blood samples.
5. Aware of the study procedures and the risks involved, and voluntarily agrees to participate by providing written informed consent.
6. Willing and able to understand the study procedures and communicate effectively with study personnel.
Minimum age
18 Years
Maximum age
59 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History or presence of any medical condition that, in the opinion of the Medical Officer, may pose an unacceptable level of risk to participants or study staff, may interfere with the interpretation of safety data obtained in the trial, or may interfere with the absorption, distribution, metabolism, or excretion of ManNAc.
2. History of hypersensitivity to ManNAc or ingredients within the formulations or, in the judgment of the Medical Officer, has a condition that places the participant at increased risk for adverse effects.
3. Ingestion of an investigational medication or a new chemical entity within 30 days or 5 half-lives (whichever is longer) prior to dosing in Period 1.
4. Treated with ManNAc, sialic acid, intravenous immunoglobulin (IVIg), and/or other supplement containing sialic acid (e.g. St. John’s Wort, sialyllactose) within 120 days prior to dosing in Period 1.
5. Unable or unwilling to refrain from the use of medications, including complementary therapies and supplements, within 5 half-lives of, or for 24 h prior to dosing (whichever is longer) until completion of all study procedures within each study period.
6. Major surgery within 4 weeks prior to the screening evaluation, or planned surgery prior to completion of all study procedures.
7. Donation of blood or blood products of 470 mL or greater within 12 weeks prior to dosing in Period 1, and/or unable or unwilling to refrain from donation from the screening evaluation until completion of all study procedures.
8. History or current evidence of alcohol abuse and/or unable or unwilling to refrain from alcohol consumption for 24 h prior to dosing until completion of all study procedures in each study period.
9. History or current evidence of drug abuse, positive urine drug screen during screening, and/or unable or unwilling to refrain ingestion of drugs of abuse from the screening evaluation until completion of all study procedures.
10. Unable or unwilling to refrain from consuming food and/or beverages that contain caffeine or other xanthines (e.g. coffee, tea, cola, energy drinks and chocolate) for 24 h prior to dosing until completion of all study procedures in each study period.
11. Unable or unwilling to refrain from the use of tobacco products for 24 h prior to dosing until completion of all study procedures in each study period.
12. Unable or unwilling to refrain from food intake from 10 h prior to dosing until the 4 h timepoint in each study period.
13. Unable or unwilling to refrain from fluid intake, aside from that given as part of study procedures, from 1 h prior to dosing until the 4 h timepoint in each study period.
14. Unable or unwilling to remain seated in an upright position from immediately prior to dosing until the 4 h timepoint in each study period.
15. Unable or unwilling to be confined to the UniSA Clinical Trial Facility for 12 hours on the specified study days and/or attend the other study visits.
16. Dietary requirements that prevent consumption of the standardised study meals.
17. Poor complier or unlikely to attend specified study days.

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 to intervention is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised 1:1:1 to receive the study treatments according to one of three treatment sequences (ABC, BCA or CAB). The randomisation schedule will be generated using computer-generated block randomisation methods.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Pharmacokinetic analysis will be based on baseline-corrected ManNAc plasma concentrations, Standard pharmacokinetic parameters will be calculated using non-compartmental methods. A linear mixed effects analysis of variance (ANOVA) models were used to perform statistical comparisons of Ln-transformed, dose-normalised pharmacokinetic data between treatment groups. The residual error (error mean square) was used to construct the 90% confidence intervals for the ratio of treatment means.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
13/07/2023
Actual
28/07/2023
Date of last participant enrolment
Anticipated
23/08/2023
Actual
9/08/2023
Date of last data collection
Anticipated
14/09/2023
Actual
15/09/2023
Sample size
Target
6
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 313869 0
Commercial sector/Industry
Name [1] 313869 0
Leadiant Biosciences Inc.
Country [1] 313869 0
United States of America
Primary sponsor type
University
Name
University of South Australia
Address
GPO Box 2471, Adelaide SA 5001
Country
Australia
Secondary sponsor category [1] 315715 0
None
Name [1] 315715 0
Address [1] 315715 0
Country [1] 315715 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313018 0
University of South Australia Human Research Ethics Committee
Ethics committee address [1] 313018 0
GPO Box 2471, Adelaide SA 5001
Ethics committee country [1] 313018 0
Australia
Date submitted for ethics approval [1] 313018 0
09/05/2023
Approval date [1] 313018 0
08/06/2023
Ethics approval number [1] 313018 0
205514

Summary
Brief summary
This research is investigating a naturally occurring compound called N-acetyl-D-mannosamine monohydrate (ManNAc). ManNAc is a sugar (monosaccharide) which is found in humans. Once in the body, ManNAc is converted to another compound called N-acetylneuraminic acid (Neu5Ac) which plays a role in the synthesis and maintenance of muscle; specifically, it facilitates a process called ‘sialylation’. It is being studied as a supplement drug to treat a condition known as GNE myopathy, a rare genetic disease which is characterised by progressive skeletal muscle wasting (atrophy) caused by a lack of sialylation. In patients with GNE myopathy, this wasting and weakness of muscle affects movement and other bodily functions resulting in disability, wheelchair use and/or incapacitation. Previous studies have shown that the administration of ManNAc can replace the important compounds that patients with GNE myopathy are lacking, and therefore may be useful in treating the disease.

While supplementation with ManNAc is a promising treatment for patients with GNE myopathy, additional information on how to best administer this sugar-like compound is needed. Two new formulations have been developed; a chewable tablet formulation and a gastroretentive tablet formulation.

This study is therefore being conducted to investigate how ManNAc is absorbed into the body when administered as the chewable tablet formulation and the floating tablet formulation, compared to the current oral solution. This information will provide pivotal data to guide the further development of ManNAc treatment strategies for patients with GNE myopathy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126698 0
A/Prof Stephanie Reuter Lange
Address 126698 0
University of South Australia
UniSA Clinical and Health Sciences
CEA-17, GPO Box 2471
Adelaide, SA, 5001
Country 126698 0
Australia
Phone 126698 0
+61 08 83021872
Fax 126698 0
Email 126698 0
stephanie.reuterlange@unisa.edu.au
Contact person for public queries
Name 126699 0
Mrs Louise Massie
Address 126699 0
University of South Australia
UniSA Clinical Trial Facility
Level 1, Bonython Jubilee Building, City East Campus
Country 126699 0
Australia
Phone 126699 0
+61 08 83021365
Fax 126699 0
Email 126699 0
unisa.researchvolunteers@unisa.edu.au
Contact person for scientific queries
Name 126700 0
A/Prof Stephanie Reuter Lange
Address 126700 0
University of South Australia
UniSA Clinical and Health Sciences
CEA-17, GPO Box 2471
Adelaide, SA, 5001
Country 126700 0
Australia
Phone 126700 0
+61 08 83021872
Fax 126700 0
Email 126700 0
CHS-CPT@unisa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No data sharing plan is in place for this study.


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.