Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000120875p
Ethics application status
Submitted, not yet approved
Date submitted
20/10/2020
Date registered
8/02/2021
Date last updated
8/02/2021
Date data sharing statement initially provided
8/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Blockade of mini-TrpRS for treatment of diabetic foot syndrome: A Prospective open-label phase 1a/1b randomized placebo-controlled trial.
Scientific title
Blockade of mini-TrpRS for treatment of diabetic foot syndrome: A Prospective open-label phase 1a/1b randomized placebo-controlled trial.
Secondary ID [1] 302839 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Foot Ulcers 319446 0
Condition category
Condition code
Skin 317415 317415 0 0
Other skin conditions
Metabolic and Endocrine 317738 317738 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To demonstrate that D-Tryptophan is safe and has pharmacokinetic tolerability and its therapy is associated with clinically significant reductions in biological markers of inflammation, wound area, and healing time compared to placebo in type 2 diabetic patients with diabetic foot ulcer (DFU).
The study will have two phases, phase 1a (single ascending dose, SAD) being the single-dose escalation part.
Based on the results of the Phase 1a trial, the study will be followed by phase 1b dose expansion part (multiple ascending doses, MAD) of the study, which will involve an increase in the number of participants and a treatment period of 12 weeks compared to placebo (control arm).
Phase 1a (SAD): one single dose (oral) in the ratio 3:1 ; drug (n=6) or placebo (n=2) in four cohorts. dosage: 200mg, 400mg, 800mg and 1200mg

Phase 1b (MAD): for this dose (oral drug) expansion part of the study; 20 in each group will be treated, totaling 80 participants for 12 weeks; 200mg (once daily for 12 weeks), 400mg (once daily, for 12 weeks), 800mg (twice 400mg per day, for 12 weeks) and 1200mg (thrice 400mg per day for 12 weeks)

Dosage Adherence: Study participants will be requested to bring trial drug bottles and study nurse will verify adherence rates and document

Standard Wound Care: The same standard of wound care will be provided to all enrolled patients throughout the study. Podiatrists will manage foot ulcers with a particular interest in wound healing and compression therapy. The subjects will self-dress their wounds three days a week and will be reviewed by a podiatrist or clinician on a fortnightly basis (Patient Visit 1– Patient Visit 7). Instructions on how to self-dress wounds will be given to patients and documented in the “additional comments section” of the “Queensland Health High-Risk Foot Form” for later comparison with what the patients did at home, as documented in their patient diaries. Dry necrotic lesions will be hydrated to promote a moist wound environment, encouraging autolytic debridement and cell migration. An atraumatic dressing and a non-adherent absorbent pad will be applied as a secondary dressing. After autolytic debridement, a conformable silver poly-membrane will be applied and retained with a light tubular support bandage. If the wound is infected, antibiotics will be administered based on microscopy, culture, and sensitivity results following deep wound swabs and blood cultures. Any antibiotics administered will also be documented in the concomitant medication section of the CRF.
Intervention code [1] 318855 0
Treatment: Drugs
Comparator / control treatment
D-Tryptophan + standard wound care compared to placebo + standard wound care.
Placebo composition: Microcellulose
Control group
Placebo

Outcomes
Primary outcome [1] 325447 0
The primary objective of this study is to assess the safety of D-Tryptophan + standard wound care compared to placebo + standard wound care in phase 1a/1b.

Safety to be assessed by the research nurse in the form of documenting Adverse Event (AE) and Serious Adverse Event (SAE) monitoring with a particular emphasis on hypoglycaemic events at every study visit except for Diabetic Visit 1 (Screening). Also, safety is specially assessed 4 +/- 1 (phase 1a) 7 +/- 2 (phase 1b) days after first study drug intake for all patients via Telephone Contact 1) with a particular emphasis on potential hypoglycaemic events which may be caused by the study drug so that the patient’s other diabetic medication may need to be adjusted. Furthermore, it is entirely up to the investigator’s discretion to decide how many additional telephone contacts will be performed for each patient between Telephone Contact 1 and Diabetic Visit 3 in order to continue monitoring for patient safety until patients reach a stable glycaemic state again and also no other safety concerns exist in the opinion of the investigator. However, patients whose blood glucose levels are not sufficiently stabilized within a reasonable time frame after first study drug intake or for whom the investigator for any other reason thinks that study drug intake may potentially be harmful should be taken off the study medication while remaining in the study’s 12-week observational follow-up program.
Timepoint [1] 325447 0
Safety will be assessed from the time of trial drug taken until 24 hours (phase 1a) and until 12 weeks (phase 1b)
Primary outcome [2] 325774 0
The second primary objective of this study is to assess the pharmacokinetic tolerability of D-Tryptophan + standard wound care compared to placebo + standard wound care for phase 1a/b

The analysis will include Pharmacokinetic parameters Cmax, Tmax, t½, AUC, AUCinf, Cl, Lambdaz, Vd, F
The bioanalytical method will be fully validated in human serum following FDA and EMA guidelines, including:
Linearity, Accuracy and precision, Dilution integrity, Sensitivity, Selectivity, Matrix effect, Recovery, Short-term stability in a matrix (bench-top stability), Freeze/thaw cycle stability, Carry-over, Batch, size, Long-term stability in a matrix at -20 and -80 °C at one and three months, Stock solution and working solution stability, Post-preparative stability of the extracted sample, Haemolysed QCs and
Whole blood stability
Timepoint [2] 325774 0
For the pharmacokinetic studies, blood samples will be collected at time points, 2,4,8, 12, and 24 hours, post dose (phase 1a) and time points 2,4,8, 12, and 24 hours and at 6 and 12 weeks post-first dose (phase 1b).
Secondary outcome [1] 387984 0

Secondary endpoints and objectives will be assessed for Phase 1b:

To assess the effect of D-Tryptophan + standard wound care compared to placebo + standard wound care has on:

1. To assess the safety of D-Tryptophan compared to placebo by comparing the frequency and severity of adverse events in the intervention and control groups using the graded using the Common Terminology Criteria for Adverse Events (CTCAE4)
Timepoint [1] 387984 0
Comparison will be performed to assess the effect of intervention for the time points; Baseline (prior to first dose), 6 weeks post-first dose and at the end of 12 weeks post-first dose.
Secondary outcome [2] 389105 0

2. The serum concentration levels of biological markers of inflammation, pro-thrombogenicity, and atherosclerosis other than interleukin-6 compared to placebo including hs-CRP, platelet reactivity, TNF-a, interleukin 1 beta (IL-1 beta), adiponectin, tissue TGF-ß1, and other markers will be assessed for Phase 1b.
Timepoint [2] 389105 0
baseline (prior to first dose), 6weeks post first dose and 12 weeks post first dose.
Secondary outcome [3] 389106 0
3. The index foot ulcer wound fluid concentration levels of biological markers of inflammation including proteases and their inhibitors, cytokines, and growth factors assessed for Phase 1b
Timepoint [3] 389106 0
baseline (prior to first dose), 6 weeks post first dose and 12 weeks post first dose.
Secondary outcome [4] 389107 0
4. The mean percentage reduction in estimated index foot ulcer wound area and wound volume compared to placebo as assessed by the change from randomization to week six and week 12 using the 3D silhouette wound measuring camera will be assessed for Phase 1b
Timepoint [4] 389107 0
baseline (prior to first dose), 6 weeks post first dose and 12 weeks post first dose.
Secondary outcome [5] 389108 0
5. To assess the effect D Tryptophan + standard wound care compared to placebo + standard wound care has on the mean total remaining index foot ulcer healing time in days as measured by the period from randomization to the day the last wound dressing was removed will be assessed for Phase 1b.
Timepoint [5] 389108 0
12 weeks post first dose
Secondary outcome [6] 389109 0
6. To describe and compare the potential differences in biological marker responses and patterns over the healing process of the index foot ulcer between serum and wound fluid markers within the same treatment arms and between treatment arms will be assessed for Phase 1b.
.
Timepoint [6] 389109 0
baseline (prior to first dose), 6 weeks post first dose and 12 weeks post first dose.
Secondary outcome [7] 389110 0
7. To compare hand-measured ulcer size measurements (width, length, depth, volume) with corresponding measurements performed with the Wound Measurements & 3D Imaging System will be assessed for Phase 1b.
Timepoint [7] 389110 0
For duration of study (12 weeks) regularly monitored every 2 weeks
Secondary outcome [8] 389111 0
8. To assess patient compliance with treatment instructions. This includes comparing patient instructions given in regards to the study medication intake in the Diabetes Clinic with the actual study medication intake at home as documented by the patient in the patient diaries as well as comparing wound dressing instructions given to patients at the Podiatry Clinic with the actual wound dressing activities at home as documented by the patient in the patient diaries, will be assessed for Phase 1b.
Timepoint [8] 389111 0
For duration of study (12 weeks) regularly monitored every 2 weeks

Eligibility
Key inclusion criteria
Inclusion Criteria:
1. Subjects greater than or equal to 18 years of age diagnosed with type 2 diabetes on diet only or any diabetic medication regime.
2. Existing diabetes index foot ulcer grade A1 or higher according to the University of Texas Wound Classification System of Diabetic Foot Ulcers on the day of study inclusion. A foot ulcer is defined as any full-thickness skin defect existing for at least 14 days. In patients with multiple diabetic foot ulcers, the index foot ulcer is defined as the foot ulcer with the largest wound area at the time of inclusion
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1) Type 1 Diabetes.
2) Current index foot ulcer of any non-diabetic pathophysiology (e.g. rheumatoid, radiation-related, vasculitis-related, calciphylaxis, or dystrophic calcinosis cutis, etc.).
3) Any major surgery up to 6 months before the day of enrolment or any planned surgery before study completion, including any major surgical intervention for the diabetic foot ulcer.
4) Significant medical conditions that potentially impair wound healing and/or alter the concentration of serum immune markers including hepatic, respiratory or cardiac failure, aplastic anemia, autoimmune diseases (e.g., Lupus erythematosus, scleroderma, etc.), chronic inflammatory diseases (e.g., inflammatory bowel disease, inflammatory or rheumatoid arthritis, etc.) and any active malignancies including cancerous or pre-cancerous lesions in the ulcer area other than basal cell carcinoma.
5) Any concomitant medication which could potentially alter the concentration of serum immune markers during the study including systemic cortocosteroids, immunosuppressants, chemotherapeutic agents, growths factor products, etc.
6) Skin and dermal substitutes within 30 days before study enrolment.
7) Enzymatic debridement treatment.
8) Active Charcot's foot as determined by clinical and radiographic examination.
9) Significant renal impairment (eGFR < 30 ml/min).
10) Pregnancy, lactation or child-bearing potential. Women must be either of non-childbearing potential as defined in the protocol or must have a negative pregnancy test on the day of study inclusion or randomization and agree to use an adequate method of contraception as defined in the protocol for at least until two weeks after taking the last dose of study medication. Also, men who take part in this study should genuinely not plan to get their partners pregnant (no active family planning) while participating in this study and until 14 days after taking the last dose of study medication.
11) Participation in any other clinical trial.
12) Inability to comply with study protocol.
13) Any current or new contraindication, special warning, precaution or other patient safety-related concern relevant to the patient at the time of enrolment as listed in the current product information.

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)
Concealed through numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The analysis will include Pharmacokinetic parameters (e.g., Cmax, Tmax, t½, AUC, AUCinf, Cl, Lamda z, Vd, F) as well as descriptive statistics (count, mean, standard deviation, standard error, %coefficient of variation (CV), minimum, median, maximum, geometric mean, and %CV of the geometric mean) which will also be reported for each of the pharmacokinetic parameters.
Missing data will be imputed using the Last Observation Carried Forward (LOCF) approach. Patients with post-randomization data will have their last study assessment carried forward as their final assessment for analyses. These will serve as conservative estimates since the patients are expected to get better over time. Analyses on Observed Cases (OC) will be performed to study the robustness of the result.
Descriptive statistics including frequency tables (including n, mean, median, standard deviation, minimum and maximum for continuous variables and n, frequency and percentage for categorical variables) and graphs will be provided for all variables, as well as for the changes from baseline within each treatment and the differences between the treatment groups at each visit, for both OC and LOCF, as appropriate.

All data will be analyzed using SPSS Version 25 or Stata 16. Tests for normality will be performed, and based on the outcome, parametric or nonparametric tests will be employed to determine the differences between the groups. The results will be given as mean + standard deviation. The chi-squared analysis will be performed for categorical variables, and student T-test or Mann Whitney U test will be carried out for continuous variables for parametric or non-parametric data, respectively. ANOVA will be used for determining differences among multiple groups. A p-value <0.05 will be considered significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2021
Actual
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
30/12/2024
Actual
Sample size
Target
112
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17848 0
The Townsville Hospital - Douglas
Recruitment postcode(s) [1] 31704 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 307001 0
Self funded/Unfunded
Name [1] 307001 0
funding to be sought
Country [1] 307001 0
Primary sponsor type
Hospital
Name
Townsville University Hospital
Address
Townsville University Hospital
100 Angus Smith Dr,
Douglas
QLD 4814
Country
Australia
Secondary sponsor category [1] 307568 0
None
Name [1] 307568 0
Address [1] 307568 0
Country [1] 307568 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307132 0
Townsville University Hospital
Ethics committee address [1] 307132 0
Ethics committee country [1] 307132 0
Australia
Date submitted for ethics approval [1] 307132 0
04/11/2020
Approval date [1] 307132 0
Ethics approval number [1] 307132 0

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

Contacts
Principal investigator
Name 106146 0
Prof Usman Malabu
Address 106146 0
Department of Endocrinology & Diabetes

Townsville University Hospital
Townsville, QLD 4814 Australia
Country 106146 0
Australia
Phone 106146 0
+61 7 4433 1420
Fax 106146 0
Email 106146 0
[email protected]
Contact person for public queries
Name 106147 0
Usman Malabu
Address 106147 0
Department of Endocrinology & Diabetes

Townsville University Hospital
Townsville, QLD 4814 Australia
Country 106147 0
Australia
Phone 106147 0
+61 7 4433 1420
Fax 106147 0
Email 106147 0
[email protected]
Contact person for scientific queries
Name 106148 0
Usman Malabu
Address 106148 0
Department of Endocrinology & Diabetes

Townsville University Hospital
Townsville, QLD 4814 Australia
Country 106148 0
Australia
Phone 106148 0
+61 7 4433 1420
Fax 106148 0
Email 106148 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
being a phase 1a study, IPD will not be share


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.