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Trial registered on ANZCTR


Registration number
ACTRN12616000548437
Ethics application status
Approved
Date submitted
18/04/2016
Date registered
28/04/2016
Date last updated
28/04/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatment of Melasma with Oral Tranexamic Acid
Scientific title
Randomised efficacy study of oral tranexamic acid for the treatment of moderate to severe melasma in adult females.
Secondary ID [1] 289036 0
nil known
Universal Trial Number (UTN)
U1111-1182-0553
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melasma 298452 0
Condition category
Condition code
Skin 298553 298553 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tranexamic acid is formulated as a tablet containing microcrystalline cellulose, purified talc, magnesium stearate, anhydrous colloidal silica, povidone, hydroxypropylcellulose, titanium dioxide, macrogol 8000, vanillin and the proprietary ingredient, Eudragit E100 (ID number 1753).

Presentation: Capsules, 250 mg: 60's (HDPE bottle)

For the purpose of this study, capsules containing 250mg of TXA will be used. 500mg TXA tablet will be halved, crushed and put into a capsule size 1 to contain 250mg of TXA. The compounding will be done via Novo Pharmacy Forrest Hill.

Treatment group: TXA 250mg twice daily, orally for 12 weeks. All patients will use sunscreen once daily to the entire face during the day. After week 12 they will stop taking the capsule and continue sunscreen for an additional 12 weeks. We will be providing all subjects with a standard sunscreen of at least SPF 30.

To monitor capsule adherence patients will be issued a fixed number of capsules between each study visits. Remaining study drug will be counted and new study drug will be dispensed if required with instructions to take TXA at the same time everyday to encourage compliance

To monitor sunscreen usage adherence, weight of sunscreen bottle will be weighed at each visit. 3g (3ml) of sunscreen should be used on the face daily
Intervention code [1] 294517 0
Treatment: Drugs
Comparator / control treatment
Control capsules used in this study will contain pure microcrystalline cellulose 210mg. Capsule size 1. Capsule colour white opaque in colour. Composition of capsule is gelatin.

Control capsules will be packaged in the same manner and quantity as the active capsules.

Control group: Control capsule twice daily, orally
Control group
Placebo

Outcomes
Primary outcome [1] 298037 0
Efficacy- Change in baseline ( week 0) in modified melasma area and severity index (MASI) after 12 and 24 weeks of treatment as compared with control
Timepoint [1] 298037 0
0, 12 and 24 weeks post commencement of intervention.
Primary outcome [2] 298054 0
Safety: Evaluating the safety of low dose tranexamic acid 250mg twice daily in the treatment of melasma.

Safety will be assessed based on reported adverse side effects ( e.g. GIT discomfort etc) and facial examination of adverse side effects ( e.g. skin photosensitivity)
Timepoint [2] 298054 0
0, 2, 4, 6, 8, 12 and 24 weeks post commencement of intervention.
Secondary outcome [1] 322988 0
Change in baseline (week 0) Mexameter readings after 12 weeks and 24 weeks of treatment as compared with control

A mexameter (narrow band reflectance spectrophotometer) will be used to measure the pigmentation of the affected and adjacent non-affected skin and digital images will be taken with a camera
Timepoint [1] 322988 0
0, 12 and 24 weeks post commencement of intervention.

Eligibility
Key inclusion criteria
1. Must provide informed consent
2. Must be between the age of 18-80 and female
3. Female of child bearing potential must have a negative pregnancy test at screening and Day 1 and be using an effective method of contraception until 28 days after taking the last dose of the study drug. Acceptable methods of contraception include, but are not limited to the following methods; monogamous relationship with vasectomized partner, or barrier methods
4. Females of non-childbearing potential as determined by having undergone of the following procedures
a. Sterilisation
b. Bilateral tubal ligation
c. Hysterectomy
d. Bilateral oophorectomy
e. Or be postmenopausal with amenorrhea for at least 1 year prior to screening
5. Moderate to severe melasma defined by the following at screening visit:
a. Modified MASI scoring
b. Mexameter readings
6. Willing and able to comply with study instructions and return to the study site for required visits
7. Must be able to comply with the study regimen for the duration of the study
Minimum age
18 Years
Maximum age
80 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Females who are pregnant or nursing, or women who are planning a pregnancy during the study
2. Women on hormonal birth control
3. Current treatment with blood thinning medications
4. Use of topical hydroquinone within 3 months of study enrolment
5. Use of topical steroids or vitamin A analogues within 1 month of study enrolment
6. History of laser or any mechanically abrading treatments to the face within 9 months of study enrolment
7. Regular use of tanning parlours, or occupation involving primarily outdoor activities
8. Additional exclusion criteria based on the TGA-approved package insert for TXA are:
a. history of thrombosis or thrombophilia
b. stroke
c. >2 spontaneous abortions
d. significant kidney dysfunction (creatinine clearance less than 40mls/min)
e. cancer
f. smoking (>8 cigarettes per year)
g. significant cardiovascular or respiratory disease (end stage congestive heart failure or chronic obstructive pulmonary disease)
h. subarachnoid hemorrhage
i. acquired disturbances of color vision
j. active thromboembolic disease such as deep vein thrombosis (DVT)
k. pulmonary embolism
l. cerebral thrombosis.
m. those who will be travelling long distances (car, train, ship or plane travel) anytime during the study period will be excluded from the study.
n. those on hormonal replacement therapy (HRT) due to increased risk of thrombosis

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)
The contents of the bottles will be unknown to both patients and investigators.
Randomisation sheets will be used to record patient information (date of randomization, Name, Age, Sex, and Ethnicity/Race) when a randomization is performed.
When doing the randomisation, either the Moderate (numbered 101-122) or Severe Melasma (numbered 201-222) sheet will be selected and the next randomization number will be used.
Patient information will be recorded; the number used on the randomization sheet will correspond to 3 "bottles" of medication.
It is very important that the correct sheet (moderate/severe) is used when a patient is randomised. The balance in the assignment of treatment groups will be lost if the incorrect sheet is used.
If incorrect sheet is used, the primary investigator needs to be notified.
The sheets link the subject number and the name and these sheets will be kept confidential in a locked cabinet at Novo pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The stratified (Moderate/Severe Melasma) randomisation is performed with a block size using SAS V 9.4 with different random number seeds for each strata; 22 cases will participate in each strata with equal numbers of active/control within each strata. When the study is over, block size will be revealed
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 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy analysis:
*The primary outcome measure to be analysed is the difference in mean Mexameter readings between involved and adjacent uninvolved skin (delta Mexameter score).
*A repeated measures analysis of compound symmetry covariance will be used to compare differences between the delta-Mexameter scores at baseline, 12 weeks, and 24 weeks between the TXA and control group.
*A similar analysis will be used to compare the modified MASI scores at baseline, 12 weeks, and 24 weeks between the 2 groups.
*The critical value for all efficacy analyses will be 0.05.

Calculating the amount of patients needed for the study:
*Although we calculated 40 patients, we are recruiting 44 patient based on an average 10% drop out rate from other studies done by our American team in this population.


Mexameter
*We expect a 30-40% change in the treatment as usual (TAU) group and 60-80% change in the pill (TAU+P) group.
*TAU = treatment as usual group or control group where they are treated with sunscreen and the control pill
*TAU + P group is TXA and sunscreen and our treatment arm
*Using the expected proportional change of 60% for TAU+Pill (48.5 to 19.4=29.1) and expected proportional change 30% for TAU (48.5 to 33.96 = 14.56) and an SD of 16.42 which should be an overestimate of the SD].
*Group sample sizes of 20 and 20 achieve 90.0% power to detect a mexameter difference between TAU vs TAU+Pill of 14.56 (29.1-14.6) in a design with 2 repeated measurements (0 and 3 months) having a Compound Symmetry covariance structure when the standard deviation is 16.42, the correlation between observations on the same subject is 0.50, and the alpha level is 0.05.


MASI
*TAU (13.31 – 9.32=3.99) TAU+Pill (13.31 – 5.32=7.99)
*Group sample sizes of 35 and 35 achieve 81.3% power to detect a difference of 4.00 (7.99-3.99) in a design with 2 repeated measurements having a Compound Symmetry covariance structure when the standard deviation is 5.13, the correlation between observations on the same subject is 0.500, and the alpha level is 0.05.


Modified MASI
*TAU (6.89 – 4.82=2.07) TAU+Pill (6.89 – 2.76=4.13)
*Group sample sizes of 35 and 35 achieve 82.8% power to detect a difference of 2.07 (4.13-2.07) in a design with 2 repeated measurements having a Compound Symmetry covariance structure when the standard deviation is 2.60, the correlation between observations on the same subject is 0.50, and the alpha level is 0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/05/2016
Actual
Date of last participant enrolment
Anticipated
18/06/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
44
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5686 0
Laser Dermatology - Box Hill

Funding & Sponsors
Funding source category [1] 293406 0
Commercial sector/Industry
Name [1] 293406 0
Rational Skin Care
Country [1] 293406 0
Australia
Primary sponsor type
Individual
Name
Dr Michelle Rodrigues
Address
Laser Dermatology, Box Hill
503 Elgar Rd, Box Hill VIC 3128
Country
Australia
Secondary sponsor category [1] 292233 0
None
Name [1] 292233 0
None
Address [1] 292233 0
None
Country [1] 292233 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294856 0
BellBerry Limited
Ethics committee address [1] 294856 0
129 Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 294856 0
Australia
Date submitted for ethics approval [1] 294856 0
07/10/2015
Approval date [1] 294856 0
17/03/2016
Ethics approval number [1] 294856 0
2015-08-541

Summary
Brief summary
Melasma is a common disorder of hyperpigmentation, primarily affecting the face. It can affect all racial types but predominately affects women with darker skin types.

The exact cause of melasma is unknown, but it is thought to be due to many things including pregnancy, hormonal contraception, and sunlight. Melasma can be very difficult to treat and often frustrating for the participant and doctor with evidence showing that it may adversely affect quality of life.

Over the past decade, there has been growing use of topical, oral and injectable TXA in Asia. More recently, clinical research in Asia has shown promising results with oral tranexamic acid for the treatment of melasma. The dose used in melasma is less than that for menorrhagia. Typically 500-750mg daily is used for melasma. Despite promising results with oral TXA for the treatment of melasma in Asian studies, none have been conducted in the western world to date.

You will be asked to come for 6 study visits. An initial screening visit will be followed (if you qualify for the study) by a review at weeks 0, 4, 8, 12 and 24. You will be randomly allocated into one of 2 arms. In the TXA group, participants will take two 250 mg tablet (this will be a 500mg tablet that will be broken into a half). This will be taken daily for 12 weeks from the baseline visit.

Participants in the placebo arm will follow an identical protocol with placebo capsule, which does not contain the active medication. All participants will use sunscreen to the entire face during the day. After week 12 participants will stop taking the medication and continue sunscreen for an additional 12 weeks. The researchers will be providing all participants with a standard sunscreen of at least SPF 30. Participants will be instructed not to use any other medications for melasma during the study period.

Although no adverse effects have been reported with TXA in pregnancy and no theoretical basis of risk exists, it has not been formally studied in pregnant women. Therefore, we requested to avoid becoming pregnant and use non-hormonal contraceptive methods during the study if you are sexually active. If pregnancy occurs please discontinue the study medication and inform the study investigators if pregnancy occurs.

This study aims to determine how effective oral tranexamic is for melasma and also assess its safety.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65234 0
Dr Michelle Rodrigues
Address 65234 0
Laser Dermatology
503 Elgar Road
Box Hill, 3128
Victoria, Australia
Country 65234 0
Australia
Phone 65234 0
+61 413 997 670
Fax 65234 0
Email 65234 0
[email protected]
Contact person for public queries
Name 65235 0
Dr Harini Bala
Address 65235 0
Laser Dermatology
503 Elgar Road
Box Hill, 3128
Victoria, Australia
Country 65235 0
Australia
Phone 65235 0
+61 420 963 483
Fax 65235 0
Email 65235 0
[email protected]
Contact person for scientific queries
Name 65236 0
Dr Harini Bala
Address 65236 0
Laser Dermatology
503 Elgar Road
Box Hill, 3128
Victoria, Australia
Country 65236 0
Australia
Phone 65236 0
+61 420 963 483
Fax 65236 0
Email 65236 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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