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Trial registered on ANZCTR


Registration number
ACTRN12615000495527
Ethics application status
Approved
Date submitted
24/04/2015
Date registered
19/05/2015
Date last updated
29/06/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A dose escalating open label study in Type 1 diabetic subjects, to assess the pharmacodynamics activity of transbuccal human recombinant insulin compared to subcutaneous human insulin.
Scientific title
A dose escalating open label study in Type 1 diabetic subjects, to assess the pharmacodynamics activity of transbuccal human recombinant insulin compared to subcutaneous human insulin.
Secondary ID [1] 286317 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
MSL001-PH-2-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes Mellitus 294415 0
Condition category
Condition code
Metabolic and Endocrine 294724 294724 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is an open label, eight arm crossover study in participants with T1DM, designed to evaluate the pharmacodynamics, pharmacokinetics, and safety of four doses of MSL-001 (the transbuccal human recombinant insulin intervention) compared to recombinant human insulin (Humulin). Transbuccal human recombinant insulin intervention is where the administration of the insulin intervention is by placing the film strips on the inner cheek.

It consists of 10 subject visits: the screening visit (V0), eight treatment visits (V1-V8), and a safety follow up visit (V9). Between each treatment visit there is a 7-21 day window allowed for adequate washing out.

At the screening visit (Day -28 to day -3) subjects will be informed about the study and sign the informed consent if they agree to participate.

Participants will check in the evening prior to each treatment visit and undergo safety assessments prior to study drug treatment.




At each treatment visit, a subject will receive a single dose of MSL-001 (the transbuccal human recombinant insulin intervention) or the comparator (subcutaneous insulin). By the end of the study, each subject will have received both formulations of MSL-001 (the transbuccal human recombinant insulin intervention) and the comparator drug. Therefore at each treatment visit, participants will receive one dose per visits of the treatments noted below.

*Comparator Arms:
Recombinant Human Insulin Subcutaneous (SC) dose 5IU
Recombinant Human Insulin Subcutaneous (SC) dose 10IU
Recombinant Human Insulin Subcutaneous (SC) dose 15IU

*Film formulations A and Formulation B (the transbuccal human recombinant insulin intervention):
Formulation A: 1 x 5IU film for 5IU dose (plus 3 placebo films)
Formulation B: 1 x 5IU film for 5IU dose (plus 3 placebo films)
Formulation A or Formulation B:1 x 15IU film for 15IU dose (plus 3 placebo films)**
Formulation A or Formulation B: 4 x 5IU films for 20IU dose (no placebo films)**
Formulation A or Formulation B: 4 x 15IU films for 60IU dose (no placebos films)**

**Following dosing with the Formulation B 5IU dose, data from the the three 5IU formulations (subcutaneous 5IU, Formulation A 5IU film and Formulation B 5IU film) will be analysed to determine which film formulation will be utilised for the remainder of the study.

Both formulations contain the same active product and the same excipients and are prepared essentially using the same process. However, the ingredient list for Formulation B includes hydropropylmethylcellulose and glycerin whereas the ingredient list for Formulation A was simplified and lacks hydropropylmethylcellulose and glycerin.


**As noted above, the mode of administration of the film strips is by placing the film strips on the inner cheek.

The duration of study participation for participants completing the study is up to 112 days. The estimated duration of the total study is approximately 6 months. The end of study is defined as the date of the last visit of the last particpant.
Intervention code [1] 291371 0
Treatment: Drugs
Comparator / control treatment
This study compares the administration of the comparator, Humulin R insulin administered subcutaneously with the study drug (MSL001) administered via transbuccal means (that is,the film will be placed on the inner cheek) at varied dose strengths.

At enrollment, all eligible participants will will have T1DM and will be on a standing insulin regimen that will include a combination of basal (that is, intermediate -long acting insulin) such as Lantu (Trademark) glargine, Levemir (Trademark) detemir, or NPH (Neutral Protamine Hage-dorn) and prandial insulin (that is short acting insulin) such as Novolo (Trademark) insulin aspart, Humalog (Trademark) insulin lispro, Apidra (Trademark)insulin glulisine, Novolin R(Trademark) regular human insulin, or any other approved similar Insulin approved in Australia, unless the participant uses an insulin pump.

All of the trial subjects using Lantu (Trademark) or Levemir(Trademark) as their basal insulin will interrupt their normal regimen at least 48 hours prior to their first dose of the IP.
Between 22 and 48 hours of receiving the IP, the only basal insulin that will be permitted is NPH. As needed, participants will receive instruction from the study Investigators regarding how to approach their insulin regimen prior to admission to the study site. All prandial insulins, including Continuous Subcuta-neous Insulin Infusion (CSII) users, will interrupt their normal insulin regimen after dinner on day -1 (relative to treatment).

At the conclusion of the treatment visits, once all assessments have been completed and participants have been fed, they will be instructed to resume their normal insulin regimen. Additional glucose monitoring will be performed to ensure that the subject is stable prior to discharge.

Adherence to the treatment will be monitored on site when administering the film strips. A visual check of the inner cheek will be performed to ensure dissolution of the product prior to allowing any water consumption. Empty packets of each strip used will be kept at site and be reviewed as part of compliance. The subcutaneous injections are performed by study nurses and physicians.
Control group
Active

Outcomes
Primary outcome [1] 294498 0
Pharmacodynamic profile of Insulin Buccal Soluble Film (MSL-001) in comparison to subcutaneous administered human recombinant insulin (Humulin).
Timepoint [1] 294498 0
Blood Sampling will occur at (in minutes) :
-15, 0, 3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 420, 480, 540, 600, 660 and 720 for measurement of insulin and c-peptide.

Glucagon (blood) samples will be collected at -15, 0, 15, 30, 60, 90 and 120 min.

Primary Outcome Measures:

Glucose Infusion Rate (GIR) of four doses of transbuccal administered Insulin Buccal Soluble Film (5IU, 15IU, 20IU, and 60IU) vs. three doses (5IU, 10IU, 15IU) of subcutaneous human recombinant insulin (Humulin Registered Trademark) as measured by area under the curve (AUC):
-for 5IU and 15IU doses AUC(0-360)
-for 20IU and 60IU doses AUC(0-720)

(measure via blood glucose samples).
Secondary outcome [1] 313464 0
Pharmacokinetic profile of MSL-001 in comparison to subcutaneous administered human recombinant insulin.
Timepoint [1] 313464 0
Blood Sampling will occur at (in minutes) :
-15, 0, 3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 420, 480, 540, 600, 660 and 720

Secondary Outcomes measures (via blood samples at the noted time points):
Plasma human insulin of four doses of transbuccal administered Insulin Buccal Soluble Film (5IU, 15IU, 20IU, and 60IU) vs. three doses (5IU, 10IU, 15IU) of subcutaneous human recombinant insulin (Humulin R (registered)) as measured by area under the curve (AUC):
-for 5IU and 15IU doses AUC(0-360)
-for 20IU and 60IU doses AUC(0-720)

Total Amount of Glucose (TAG) Infused:
-TAGi(0-360) for 5IU and 15IU doses
-TAGi(0-720) for 20IU and 60IU doses
-AGi (0-30; 30-60; 60-90; 90-120; 120-240; 240-360) for all doses.
GIRmax; tmaxGIR for all doses
Cmax, tmax, MRT after transbuccal GNP-I insulin application
for all doses.
Secondary outcome [2] 313466 0
To evaluate the safety of MSL-001.
Timepoint [2] 313466 0
The following will be assessed: - Vital Signs:Vital signs will include body temperature (oral), BP, respiration rate, and pulse rate. Vital signs will be measured at each study visit at check in, pre dose and prior to discharge (each study day). Blood pressure will be obtained using calibrated sphygmomanometers or automated blood pressure measurement equipment. All vitals should be performed with the subject in a semi supine position after five minutes resting. If the first reading is out of range, then two more readings are taken and the lower of the two additional readings are to be used. - 12-lead Electrocardiogram (ECG):A standard 12-lead ECG will be recorded after 5 minutes with the subject in a semi supine position at screening, Visit 1 (pre and post dose at Visit 1, post dose being within 15 minutes of when the euglycemic clamp is finished) and at Visit 9. The following parameters will be recorded from the subject’s ECG trace: heart rate, QTcF interval, PR interval, QRS interval, and RR interval. - Standard laboratory safety parameters: Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis will be taken at all study visits. - Incidence of AEs will be reviewed at all study visits both during the assessments and in comparison since the last visits. The AE term, start and stop dates, severity, action taken with study drug, and outcome, will be documented, along with the Investigator’s opinion of the causal relationship between the event and the study drug. The most likely expected events are as follows. These are considered to be minor: *Hypoglycemic and Hyperglycemic events: Hypoglycemic events are a sudden drop in a subject’s blood glucose level below 70 mg/dL (3.9 mmol/L).Hyperglycemia is an increase in a subject’s blood glucose level above 200 mg/dL (11.1 mmol/L).These events are expected to be minor. *Irritation of the buccal mucosa:Application of the adhesive strips to the buccal mucosa may cause irritation. *Allergic reaction:An allergic reaction may occur against the components of the investigational product (IP) including the material used to make the buccal strips or the adhesive. *Risks Associated with Study Procedures:Minor risks are associated with catheter insertions and frequent blood draws including hematoma, infections, vasovagal reaction, or anxiety. *Possible Interactions with Concomitant Medical Treatments: Diabetic subjects are frequently on concomitant medication such as insulin and medications for complications related to their disease. However, the inert nature of glycan coated GNPs would suggest minimal or manageable interactions with concomitant medications in subjects suffering from insulin-dependent diabetes mellitus.
Secondary outcome [3] 314629 0
To evaluate tolerability of MSL-001.
Timepoint [3] 314629 0
The following will be assessed: - Vital Signs:Vital signs will include body temperature (oral), BP, respiration rate, and pulse rate. Vital signs will be measured at each study visit at check in, pre dose and prior to discharge (each study day). Blood pressure will be obtained using calibrated sphygmomanometers or automated blood pressure measurement equipment. All vitals should be performed with the subject in a semi supine position after five minutes resting. If the first reading is out of range, then two more readings are taken and the lower of the two additional readings are to be used. - 12-lead Electrocardiogram (ECG):A standard 12-lead ECG will be recorded after 5 minutes with the subject in a semi supine position at screening, Visit 1 (pre and post dose at Visit 1, post dose being within 15 minutes of when the euglycemic clamp is finished) and at Visit 9. The following parameters will be recorded from the subject’s ECG trace: heart rate, QTcF interval, PR interval, QRS interval, and RR interval. - Standard laboratory safety parameters: Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis will be taken at all study visits. - Incidence of AEs will be reviewed at all study visits both during the assessments and in comparison since the last visits. The AE term, start and stop dates, severity, action taken with study drug, and outcome, will be documented, along with the Investigator’s opinion of the causal relationship between the event and the study drug. The most likely expected events are as follows. These are considered to be minor: *Hypoglycemic and Hyperglycemic events: Hypoglycemic events are a sudden drop in a subject’s blood glucose level below 70 mg/dL (3.9 mmol/L).Hyperglycemia is an increase in a subject’s blood glucose level above 200 mg/dL (11.1 mmol/L).These events are expected to be minor. *Irritation of the buccal mucosa:Application of the adhesive strips to the buccal mucosa may cause irritation. *Allergic reaction:An allergic reaction may occur against the components of the investigational product (IP) including the material used to make the buccal strips or the adhesive. *Risks Associated with Study Procedures:Minor risks are associated with catheter insertions and frequent blood draws including hematoma, infections, vasovagal reaction, or anxiety. *Possible Interactions with Concomitant Medical Treatments: Diabetic subjects are frequently on concomitant medication such as insulin and medications for complications related to their disease. However, the inert nature of glycan coated GNPs would suggest minimal or manageable interactions with concomitant medications in subjects suffering from insulin-dependent diabetes mellitus.

Eligibility
Key inclusion criteria
1. Age between 18 and 55 years
2. Body mass index (BMI) equal to or great than 18 kg/m2 and equal to or less than 30 kg/m2.
3. Diagnosis of T1DM made at least 2 years prior to study screening day, on an insulin pump or multiple insulin injections daily.
4. HbA1c at screening less than 10 percent.
5. Subject understands the study requirements and the treatment procedures, and is willing to comply with all specified follow-up evaluations, and provides written Informed Consent before any study-specific tests or procedures are performed.
6. Subject is C- peptide negative (less than 0.2 nmol/L) on screening.
7.Female subjects must be 1 year post-menopause, surgically sterile, or if sexually active, using an acceptable method of contraception to prevent pregnancy for the duration of the study (from the time they consent until 4 weeks after the last dose of the IP). Post menopause is defined as complete cessation of menstruation for 12 months.

Women of childbearing potential must have a negative urine pregnancy test at screening and at check-in (Day-1). Female subjects must not become pregnant during the study and so must be confirmed as surgically sterile (based on documented hysterectomy or bilateral tubal ligation),
Male partner sterilization (vasectomy with documentation of azoospermia), sexually inactive by abstinence or use following contraceptive methods from the time of the first dose of study treatment until at least 4 weeks after the final dose of study treatment.
- Abstinence: Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, through the dosing period, and for at least 4 weeks after the last dose of study treatment.

- Contraceptive Methods: Use of two of the following: Hormonal Contraceptives (oral, injectable, implant, patch, ring), Barrier Contraceptives (condom or diaphragm) or Intrauterine device.
8.Male subjects, if sexually active, must agree to use condoms during intercourse for the duration of the study and for 3 months after the last dose of study treatment. Male subjects must not donate sperm for the duration of the study period and for 3 months after the last dose of study treatment.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of drug or alcohol abuse in the opinion of the Investigator.
2. History of severe or multiple allergies in the opinion of the Investigator.
3. Treatment with any investigational drug/device within 1 month or 5 half-lives of the IP (whichever is longer) prior to screening.
4. Progressive fatal disease.
5. History of significant cardiovascular, respiratory, gastrointestinal, hepatic, neurological, psychiatric and/or hematological disease defined at the discretion of the Investigator.
6. History or evidence of renal impairment of greater than Chronic Kidney Disease (CKD) stage 2.
7. Pregnant or lactating woman.
8. Lack of compliance or other similar reason that, according to Investigator, precludes satisfactory participation in the study.
9. History of Coronary Artery Bypass Graft (CABG), Myocardial Infarction (MI), active Ischemic heart disease, or Class II or greater congestive heart failure.
10. History of Cardiovascular Accident (CVA) or Transient Ischemic Accident (TIA).
11. Hypertension (blood pressure greater than 140/90 mm Hg) at screening (BP may be repeated up to 2 additional times after five minute semi supine rest period with the lowest BP taken as the measurement).
12. Low blood hemoglobin concentration equal to or less than 12 g/dL for female and equal to or less than 13 g/dL for male, at screening.
13. Psychological incompetence, whereby subject is assessed as being unable to provide information, consent, or comply with study requirements and procedures in the opinion of the Investigator.
14. Diminished skin integrity at the relevant injection sites in particular the abdomen.
15. Involved in or planned to participate in other studies that may interfere in data collection in the opinion of the Investigator.
16. Unstable blood glucose levels at the discretion of the Investigator.
17. Daily insulin requirements greater than 80 IU
18. Any significant secondary complications of diabetes including neuropathy, ketoacidosis, nephropathy, cardiovascular disease, stroke, and retinopathy as defined by the Investigator.
19. Experienced more than one episode of severe hypoglycemia in past 6 months requiring hospital intervention
20. Suffered more than one episode of Diabetic Ketoacidosis (DKA) in the past 6 months requiring hospital intervention.
21.Any other reason that, in the opinion of the Investigator, the volunteer is unsuitable to participate

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)
The Principal Investigator will keep a record, the subject screening log, of subjects who entered pre-study screening.
The Investigator(s) will:
1. Obtain signed informed consent from the potential subject and/or their guardian/legal representative before any study specific procedures are performed.
2. Determine subject eligibility.
3. Assign eligible subjects a unique code.

Participants will be numbered sequentially by the site. The numbering format will be a site number (as allocated by the eCRF system) and a sequential participant number.

Replacement participant will be given the next sequential number (as this is not a randomized study).

If a participant withdraws from participation in the study, then his/her enrolment code cannot be reused.

Codes will be assigned strictly sequentially as participants become eligible. Drop outs/withdrawals may be replaced after agreement from the sponsor. Replacement participants will have the same treatment sequence as the dropout participants.


Participants will be numbered sequentially by the site. The numbering format will be a site number (as allocated by the eCRF system) and a sequential subject number. Replacement participants will be given the next sequential number (as this is not a randomized study).

Methods for Assigning Treatment Groups:
All participants will be, assigned to the same consecutively escalating doses to be administered at each chronological visit by the study personnel or in accordance to the treatment scheduled detailed in the study protocol.
Allocation is not concealed for the treatment scheduling of participants, however as noted, participants themselves are blinded to their treatment at each visit.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
This is an open label study. For transbuccal test items participants will however be blind to the actual dose administered since four (4) strips will always be placed in the participants mouth which will comprise both blank and active strips, the number of each depending on the total dose being administered.
Phase
Phase 2
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
The analysis will focus on exploratory and descriptive data analysis. The evaluation will be specified in the statistical analysis plan (SAP).

The sample size will be 12 participants, up to 18 participants can be enrolled. Given the exploratory pilot nature of the study, this evaluation is performed to generate data sets for proof of concept only. Data from this study may later be used for power calculation for further Phase IIb confirmatory follow up studies.

The demographics characteristics such as age, gender, ethnic origin etc. will be summarized in frequency tables according to their level of measurement. Continuous data will be summarized by the mean value, standard deviation, minimum and maximum value, 25th and 75th percentile, the median, and the number of valid values (valid N). Categorical data will be summarized by the number of valid values per category and the corresponding percentages.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 9349 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 290908 0
Commercial sector/Industry
Name [1] 290908 0
Clinical Network Services (CNS) Pty Ltd.
Address [1] 290908 0
Level 4/ 88 Jephson Street
Toowong, QLD , 4066
Country [1] 290908 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Midatech Pharma Pty Ltd:
Address
c/o Griffith Hack Consulting, Floor 15, HSBC Building, 300 Queen Street, Brisbane City, QLD 4000
Country
Australia
Secondary sponsor category [1] 289588 0
Commercial sector/Industry
Name [1] 289588 0
MonoSol Rx
Address [1] 289588 0
MonoSol Rx, LLC
6560 Melton Road
Portage, IN 46368 USA
Country [1] 289588 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292509 0
Bellberry Ethics Committee
Ethics committee address [1] 292509 0
Bellberry Limited
129 Glen Osmond Road
Eastwood SA 5063
Australia
Ethics committee country [1] 292509 0
Australia
Date submitted for ethics approval [1] 292509 0
25/02/2015
Approval date [1] 292509 0
11/05/2015
Ethics approval number [1] 292509 0
2015-02-127

Summary
Brief summary
This study is a single site, open label, cross-over, eight arm study to compare the effect of treating subjects with type 1 diabetes mellitus (T1DM) using a film (via the inner cheek) to deliver recombinant human insulin and standard subcutaneous insulin administration. Participants will receive three (3) comparator arm treatments versus five (5) investigational product arms over approximately six (6) month study participation period. Twelve (12) patients will be recruited for the study, with the possibility of eighteen (18) patients being required.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 55566 0
Dr Janakan Krishnarajah
Address 55566 0
Linear Clinical Research
Level 1, B Block
QEII Medical Centre
Hospital Avenue
Nedlands, WA, 6009
Country 55566 0
Australia
Phone 55566 0
+61 (0)8 6382 5100
Fax 55566 0
+61 (0) 8 9381 4453
Email 55566 0
JKrishnarajah@linear.org.au
Contact person for public queries
Name 55567 0
Miss Liisa Bevan
Address 55567 0
Linear Clinical Research
Level 1, B Block
QEII Medical Centre
Hospital Avenue
Nedlands, WA, 6009
Country 55567 0
Australia
Phone 55567 0
+61 (0)8 6382 5100
Fax 55567 0
+61 (0) 8 9381 4453
Email 55567 0
LBevan@linear.org.au
Contact person for scientific queries
Name 55568 0
Dr Janakan Krishnarajah
Address 55568 0
Linear Clinical Research
Level 1, B Block
QEII Medical Centre
Hospital Avenue
Nedlands, WA, 6009
Country 55568 0
Australia
Phone 55568 0
+61 (0)8 6382 5100
Fax 55568 0
+61 (0) 8 9381 4453
Email 55568 0
JKrishnarajah@linear.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary