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Trial registered on ANZCTR


Registration number
ACTRN12618001084279
Ethics application status
Approved
Date submitted
30/04/2018
Date registered
28/06/2018
Date last updated
1/11/2018
Date data sharing statement initially provided
1/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Cyclosporin for moderate to severe alopecia areata and tofacitinib extension
Scientific title
A randomised, double-blind, placebo-controlled study to evaluate the efficacy of cyclosporin in subjects with moderate to severe alopecia areata with roll-over extension phase to evaluate efficacy of tofacitinib
Secondary ID [1] 294473 0
CYC001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alopecia areata 307234 0
Condition category
Condition code
Skin 306351 306351 0 0
Dermatological conditions
Skin 306710 306710 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Cyclosporin 2mg/kg twice daily orally for 12 weeks.

Cyclosporin is an immunosuppressant agent of the class of calcineurin inhibitors and inhibits T-cell activation. It has been used to alone or with low-dose corticosteroids in the prophylaxis of organ rejection following solid organ transplants. Beneficial effects of cyclosporin therapy have also been shown in some cases of nephrotic syndrome, rheumatoid arthritis, psoriasis and atopic dermatitis.

Cyclosporin is a treatment option for patients with alopecia areata, however has only been studied in retrospective reviews, uncontrolled single-arm trials and case series. These studies show a promising effect of cyclosporin in alopecia areata.

It is currently used for atopic dermatitis and psoriasis at doses up to 2.5mg/kg/day.



Extension Phase Intervention: Tofacitinib 5mg twice daily orally for 12 weeks.

Tofacitinib is a JAK inhibitor. It is currently a medication used for rheumatoid arthritis at the same dose. Beneficial effects of tofacitinib on alopecia areata have been demonstrated in case series. These studies show a promising effect on hair regrowth. This medication will be investigated in the extension phase of this clinical trial in all non-responders. The extension phase is an open-label, uncontrolled, single-arm pilot study. All participants of the extension phase receive tofacitinib; there is no placebo. Only non-responders (defined as less than 50% improvement in hair loss) at the end of the parent study will be eligible for the extension phase. Adherence will be monitored by counting drug tablet return.
Intervention code [1] 300767 0
Treatment: Drugs
Comparator / control treatment
Control: Placebo (Flocel PH-102 2mg/kg twice daily orally) for 12 weeks

The placebo capsules will be taken in the same dosage, frequency and duration as the intervention, cyclosporin. The placebo capsules contain 2mg/kg Flocel PH-102. The capsules are made of white gelatin.

The placebo capsules will be the same shape, size and colour as the cyclosporin capsules.

Subjects will be randomised to cyclosporin or matching placebo in a 1:1 ratio.
Control group
Placebo

Outcomes
Primary outcome [1] 305711 0
Primary Objective: To evaluate the efficacy of cyclosporin compared to placebo at Week 12 in patients aged 18 to 65 years with moderate to severe alopecia areata.

Primary Endpoint: Change from baseline of Severity of Alopecia Tool (SALT) score at Week 12
Timepoint [1] 305711 0
Week 12 post-treatment initiation
Secondary outcome [1] 346219 0
Secondary objective: To evaluate the efficacy of cyclosporin on additional efficacy endpoints in patients aged 18 to 65 years with moderate to severe alopecia areata

Secondary endpoints (composite outcome):
•Change from baseline of quantified non-vellus hair counts by macrophotography at Week 12
•Proportion of responders achieving at least 1 grade improvement in numerical rating scale (NRS) for eyelash at Week 12
•Proportion of responders achieving at least 1 grade improvement in NRS for eyebrow at Week 12
Timepoint [1] 346219 0
Week 12 post-treatment initiation
Secondary outcome [2] 346220 0
Secondary objective: To evaluate the effect of cyclosporin compared to placebo on quality of life at Week 12 in patients aged 18 to 65 years

Secondary endpoints (composite outcome):
•Change from baseline in Assessment of Quality of Life-8D (AQoL-8D) score at Week 12
•Change from baseline in Alopecia Areata Symptom Impact Scale (AASIS) score at Week 12
Timepoint [2] 346220 0
Week 12 post-treatment initiation
Secondary outcome [3] 346221 0
Secondary objective: To evaluate the safety and tolerability of cyclosporin over time in patients aged 18 to 65 years with moderate to severe alopecia areata

Secondary endpoints (composite outcome):
•Incidence of treatment-emergent patient-reported adverse events (AEs)
•Incidence of specific clinical laboratory abnormalities including but not limited to anaemia, neutropenia, thrombocytopenia, lymphopenia, changes in lipid profile, and liver function tests (LFTs) on blood tests
Timepoint [3] 346221 0
Week 12 post-treatment initiation
Secondary outcome [4] 353503 0
Secondary Objective: To evaluate the efficacy of tofacitinib at Week 24 in non-responder patients aged 18 to 65 years with moderate to severe alopecia areata. Secondary Endpoint: Change from baseline of Severity of Alopecia Tool (SALT) score at Week 24
Timepoint [4] 353503 0
Week 24

Eligibility
Key inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
3. Male or female subjects between 18 to 65 years of age, inclusive, at time of informed consent.
4. Female subjects (except those at least 2 years post-menopausal or surgically sterile) with a negative serum pregnancy test during screening and a negative urine pregnancy test at baseline.
5. Male subjects able to father children and female subjects of childbearing potential must agree to the use of highly effective contraception (methods which result in low failure rate, i.e. less than 1% per year, when used consistently and correctly) throughout the study and until 30 days after the last dose of assigned treatment.
6. Must meet the following alopecia areata criteria:
a. Have a clinical diagnosis of moderate to severe alopecia areata (at least 50% hair loss of the scalp without evidence of hair regrowth within 6 months) at the screening and baseline visits;
b. Current episode of hair loss at most 7 years.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Subjects with any of the following characteristics/conditions will not be included in the study:
1. Other acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
2. Subjects have other types of alopecia (including but not limited to traction, scarring, androgenetic alopecia).
3. Currently have active forms of other inflammatory skin diseases or evidence of skin conditions (e.g. psoriasis, seborrheic dermatitis, lupus) at the time of Screening or Day 1 that in the opinion of the investigator would interfere with evaluation of AA or response to treatment.
4. Have received any of the following treatment regimens specified in the timeframes outlined below:
a. Within 6 months of first dose of study drug:
i. Any cell-depleting agents including but not limited to rituximab: within 6 months of first dose of study drug, or 5 half-lives (if known), or until lymphocyte count returns to normal, whichever is longer.
b. Within 12 weeks of first dose of study drug:
i. Cyclosporin
ii. Biologics: within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
c. Within 8 weeks of first dose of study drug:
i. Systemic treatments that could affect AA within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
ii. Use of oral immune suppressants (e.g. azathioprine, methotrexate, systemic corticosteroids, mycophenolate-mofetil) within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
iii. Intralesional steroid injection within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
iv. Participation in other studies involving investigational drug(s) within 8 weeks of first dose of study drug or within 5 half-lives (if known), whichever is longer.
d. Within 6 weeks of first dose of study drug:
i. Have been vaccinated with live or attenuated live vaccine.
e. Within 4 weeks of first dose of study drug:
i. Ultra-Violet B (UVB) phototherapy and/or Psoralen Ultra-Violet A therapy.
f. Within 2 weeks of first dose of study drug:
i. Topical treatments that could affect AA (e.g. steroid cream, medicated shampoo, herbal hair care that could affect AA).
5. Female subjects of childbearing potential and fertile male subjects who are unwilling or unable to use highly effective contraception as outlined in this protocol for the duration of the study and for at least 30 days after the last dose of investigational product.
6. Pregnant or breastfeeding female subjects
7. Have current or recent history of clinically significant severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiovascular, psychiatric, immunologic/rheumatologic or neurologic disease; or have any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or interfere with the interpretation of study results; or in the opinion of the investigator, the subject is inappropriate for entry into this study, or unwilling/unable to comply with study procedures.
8. Have a history of any lymphoproliferative disorder such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic or lymphoid disease.
9. Have current active herpes simplex infection
10. Have a history of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator within 6 months prior to Day 1.
11. A Screening 12-lead electrocardiogram (ECG) that demonstrates clinically significant abnormalities requiring treatment (e.g. acute myocardial infarction, serious tachy- or brady-arrhythmias) or that are indicative of serious underlying heart disease (e.g. cardiomyopathy, major congenital heart disease, low voltage in all leads, Wolff-Parkinson–White syndrome).
12. Have a known immunodeficiency disorder or a first-degree relative with a hereditary immunodeficiency.
13. Have any malignancies or have a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
14. Require treatment with prohibited concomitant medication(s) (Appendix 8: Prohibited Concomitant Medications) or have received a prohibited concomitant medication within 7 days or 5 half-lives (whichever is longer) prior to Day 1.
15. History of human immunodeficiency virus (HIV) or positive HIV serology at screening.
16. Infected with hepatitis B or hepatitis C viruses.
17. Subjects with a history of hypersensitivity or allergies to any ingredient of the study medication.
18. ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat, if deemed necessary:
a. Absolute neutrophil count of <2.5 x 109/L (<2500/mm3);
b. Haemoglobin <10.0 g/dL or haematocrit <30%;
c. Platelet count below the lower limit of normal (LLN) at Screening;
d. Absolute lymphocyte count of <0.5 x 109 /L (<500/mm3);
e. Serum creatinine > upper limit of normal (ULN) or eGFR <90 ml/min/1.73m2 based on the age appropriate calculation;
f. Enzymes aspartate transaminase (AST) or alanine transaminase (ALT) values >2 times the ULN;
g. Total bilirubin 1.5 times or more the ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is not more than the ULN;
h. In the opinion of the investigator, have any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the subject’s participation in the study.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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)
VIC
Recruitment hospital [1] 10818 0
Sinclair Dermatology - East Melbourne
Recruitment postcode(s) [1] 22558 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 299097 0
Charities/Societies/Foundations
Name [1] 299097 0
Australia Alopecia Areata Foundation
Address [1] 299097 0
AAAF
PO Box 5029
FRANKSTON SOUTH VIC 3199
AUSTRALIA
Country [1] 299097 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sinclair Dermatology
Address
2/2 Wellington Parade
East Melbourne
VIC 3002
Country
Australia
Secondary sponsor category [1] 298347 0
Individual
Name [1] 298347 0
Prof Rodney Sinclair
Address [1] 298347 0
Samson Clinical Pty Ltd
2/2 Wellington Parade
East Melbourne
VIC 3002
Country [1] 298347 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300032 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 300032 0
Bellberry Limited
129 Glen Osmond Road
Eastwood South Australia 5063
Ethics committee country [1] 300032 0
Date submitted for ethics approval [1] 300032 0
Approval date [1] 300032 0
30/04/2018
Ethics approval number [1] 300032 0

Summary
Brief summary
This study will investigate cyclosporin in AA. This randomised, double-blind, parallel group, study will enrol a maximum of 38 subjects. The study will be conducted at Sinclair Dermatology.

Subjects who have moderate to severe AA (at least 50% hair loss of the scalp without evidence of hair regrowth within the previous 6 months; current episode of fixed hair loss up to 7 years) present at the screening and baseline visits will be included in the study.

Subjects will be randomised to cyclosporin or matching placebo in a 1:1 ratio. Investigators and subjects will be blinded as to treatment group. Subjects will be screened within the 35 days prior to the first dose of study drug to confirm that they meet the subject selection criteria for the study. The 12-week treatment period is followed by a 4-week follow up period after the last dose of investigational product.

Non-responders will be eligible to participate in the extension phase of this clinical trial, investigating open-label tofacitinib.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82326 0
Prof Rodney Sinclair
Address 82326 0
Sinclair Dermatology
2/2 Wellington Parade
East Melbourne VIC 3002
Country 82326 0
Australia
Phone 82326 0
+61 3 9654 2426
Fax 82326 0
Email 82326 0
rodney.sinclair@sinclairdermatology.com.au
Contact person for public queries
Name 82327 0
Ms Katie Zam
Address 82327 0
Sinclair Dermatology
2/2 Wellington Parade
East Melbourne VIC 3002
Country 82327 0
Australia
Phone 82327 0
+61 3 9013 0099
Fax 82327 0
Email 82327 0
Katie.Zam@sinclairdermatology.com.au
Contact person for scientific queries
Name 82328 0
Ms Laita Bokhari
Address 82328 0
Sinclair Dermatology
2/2 Wellington Parade
East Melbourne VIC 3002
Country 82328 0
Australia
Phone 82328 0
+61 3 9013 0099
Fax 82328 0
Email 82328 0
laita.bokhari@sinclairdermatology.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Summary data but not individual participant data will be published.
What supporting documents are/will be available?
No other documents available
Summary results
No Results