A Three arm, multicenter, randomized, double blind, placebo and SOC-controlled study to evaluate the Safety and efficacy of Apremilasttopical gel, 2% w/w in adult patients with mild to moderate plaque psoriasis: Phase III clinical trial

Title of the study

A Three arm, multicenter, randomized, double blind, placebo and SOC controlled study to evaluate the Safety and efficacy of Apremilast topical gel, 2%w/w in adult patients with mild to moderate plaque psoriasis: Phase III clinical trials

|Study Type

Phase III clinical trials

|Regulatory Submission

DCGI

|Study Design

Randomized, Double Blind, Placebo and SOC controlled, Three arm, Parallel Assignment.

|Background

Information

Psoriasis is a chronic, immune-mediated, inflammatory disease characterized by distinctive, red, raised skin lesions with adherent silvery scales. This disorder affects approximately 1% –3% of the population worldwide. Psoriasis lesions most commonly appear on the elbows, knees, scalp, and trunk and may persist for months, for years, or throughout the patient’s life. These lesions can cause physical symptoms of itching, flaking, redness, and pain. Visually apparent skin lesions and the associated discomfort caused by these plaques contribute to significant impairments in patients quality of life. Furthermore, psoriasis is associated with multiple physical and psychological comorbidities, and afflicted patients have a higher risk than the general population for conditions such as psoriatic arthritis, metabolic syndrome and cardiovascular disease. Psoriasis is a lifelong recurrent disease that often requires ongoing treatment to reduce disease symptoms, improves quality of life, and maintains remission. Chronic plaque psoriasis is the most common form of the disease accounting for 85-90% of cases and appears as raised, red patches covered with a silvery white buildup of dead skin cells or scale. These patches or plaques most often appear on the scalp, knees, elbows and lower back. Topical agents are often used as a first-line therapy in the treatment of limited (mild to moderate) plaque psoriasis. These include salicylic acid, steroids, Vitamin-D analogues (such as calcipotriol), tazarotene, dithranol, coal tar extracts and combination of any of these agents. Phototherapy with Ultraviolet B (UVB) or psoralen + Ultraviolet A (UVA) is often used as a first-line treatment of widespread lesions; it is also used as second-line treatment when topical therapy is insufficient. Systemic therapy with retinoids with or without combination with UV-light, methotrexate and cyclosporine A are indicated in severe forms of psoriasis, and in patients with widespread plaque lesions. Systemic therapy may also be indicated in patients with limited but very disabling lesions (e.g. hand psoriasis).

|Study Rationale

At present, the main effective agents to manage and/or treat the plaque psoriasis are corticosteroids and are available as oral and topical preparations. The efficacy of topical corticosteroids in controlling acute symptoms of psoriasis is well established in the short term with good tolerability in general and potential side effects limit their use in the long-term. Although uncommon, long-term use is complicated by possible side effects of local skin changes, tachyphylaxis, and hypothalamic-pituitary adrenal axis suppression (CPGC, 2009). A wide range of adverse effects caused by long term corticosteroid therapy had lead to searching for other newer alternative drugs with higher safety profile. While targeting the PDE4, a common approach, for the treatment of psoriasis, the problem is the associated side effects such as emesis. In addition, PDE inhibitors can lead to vomiting, nausea, arteritis and immunosuppression. These effects are exacerbated with systemic deliveries of the PDE inhibitor and leads to problems in the brain, gastrointestinal tract, arteries or whole body. One solution to these systemic side effects is the use of a topical treatment. Hence topical formulation of Apremilast (PDE4 inhibitor) is being developed with the intention to prevent systemic exposure and restrict the medicine to areas of lesion.

|Objectives

1.               To evaluate the clinical safety and efficacy and the patient’s quality of life of Apremilast Topical Gel 2%w/w twice daily (BID) compared to placebo and SOC (Calcipotriol ointment, 0.005%w/w), in adult patients with mild to moderate plaque psoriasis during the 12 week treatment.

2.           The secondary objective of the study is to establish the pharmacokinetic and adverse effects profile of topically administered Apremilast gel 2% w/w  twice daily (BID).

|Inclusion Criteria

1.     Males or females, ≥ 18 years of age at the time of signing the informed consent document.

2.     Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.

3.     Able to adhere to the study visit schedule and other protocol requirements.

4.     Diagnosis of chronic mild to moderate plaque psoriasis i.e., 6 point sPGA score of ≤ 3 and PASI score of ≤ 10 for at least 6 months with multiple treatable areas (i.e. the lesion should not only on the face, scalp, genitals or skin folds) which covers less than 10% of the total Body Surface Area (BSA), and affected area on the limb and/or trunk ≥ 1% BSA. Must be in general good health (except for psoriasis) as judged by the Principal investigator, based on medical history, physical examination, and clinical laboratories.

5.     Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or non latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on investigational product and for at least 28 days after the last dose of investigational product.

|Exclusion Criteria

1.     Patients using topical psoriasis medications within the past 2 weeks, use of photo therapy and those taking systemic (oral, intravenous, intramuscular, or intradermal) medications for psoriasis in the past 28 days, those using steroids, immunosuppressive medications, and cyclooxygenase-2 anti-inflammatory drugs, and those using any medication conflicting with the product ingredients will also excluded from this study

2.     Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she participates in the study.

3.     Any condition, including other inflammatory diseases or dermatologic conditions, which confounds the ability to interpret data from the study, including other types of psoriasis (i.e., erythrodermic, guttate, inverse, or pustular psoriasis), other than plaque psoriasis.

4.     Prior history of suicide attempt at any time in the subject’s life time prior to signing the informed consent and randomization, or major psychiatric illness requiring hospitalization within the last 3 years prior to signing the informed consent.

5.     Women planning to become pregnant at the start of the study and pregnant or lactating women or women not taking medically approved birth control will be excluded.

6.     Active substance abuse or a history of substance abuse within 6 months prior to signing the informed consent.

7.     Exclude the patients who exhibited weight loss ≥ 5% of initial body weight.

8.     Patients participating in any other clinical trials simultaneously will be excluded from the study.

9.     Prolonged sun exposure or use of tanning booths, which may confound the ability to interpret data from the study.

10. Patients who are under treatment with apremilast and may include after wash out period.

11. In the opinion of the investigator, the subjects were not considered appropriate candidates.

|Study End Points

EFFICACY:

Primary End Points:

1.               Mean Percentage Change from Baseline in the 6 point static sPGA scale at week 8 and 12.

2.               Mean Percentage Change From Baseline in Psoriasis Area Severity Index (PASI) at Week 8 and 12.

3.               Mean Percentage Change from Baseline in erythema, scale and elevation on a 3-point Visual Analog Scale (VAS) at week 8 and 12.

Secondary End Points:

1.               Mean Change from Baseline in the Dermatology Life Quality Index (DLQI) Total Score at Week 8 and 12.

2.               Safety and tolerability throughout study period.

3.               Demonstration of systemic exposure of Apremilast at anticipated Cmax in a sub-group of subjects.

4.               Photographs of identified psoriasis lesions of a sub-set of patients on Day 0 and Day 84.

|Dosing

Intervention drug: Apremilast gel (2% w/w) twice daily for 12 weeks

Placebo comparator: Placebo vehicle twice daily for 12 weeks

SOC (Calcipotriol ointment, 0.005%w/w Calcipotriol ointment, 0.005%w/w twice daily for 12 weeks

Washout phase/Run in period: Application of non-medicated emollient for two weeks (Days-14 to Day-1)

Method of Gel Application with Instructions:

Treatment applied as a thin layer to all affected areas (Multiples of one fingertip unit (FTU) spread is recommended over the affected lesions {One FTU for approx. 100 cm2 skin surface}) twice daily maximally for up to 12 weeks after the sPGA Score on 6- point scale becoming zero i.e., the lesions found to be completely cleared whichever comes first. Application to be continued for a minimum of 8 weeks regardless of clearance of lesions during this period. Patient will be advised to wear appropriate protective clothing and take measures to avoid sun exposure to the treated area.

Manufactured and Distributed by: Aizant Drug Research Solutions Pvt. Ltd., Survey No 172/173, Apparel Park Road, Dulapally Village, Dundigal- Gandimaisamma Mandal, Medchal-Malkhajgiri District, Hyderabad – 500 100, Telangana, India.

|Visit Details

Visit 1: (2 weeks depending upon the ongoing treatment at the time of signing the consent) – Criteria Check / Informed Consent / Screening /Medication history for the past 30 days.

Visit 2: (Day -14 to Day -1) Wash-out phase. Application of nonmedicated emollient is allowed throughout the wash- out phase / Distribution of Patient diary Cards (PDCs).

*Emollient  or an alternate equivalent product will be provided.

Visit 3: Week 0 (Day 0) – Criteria Check / Randomization (1:1) /

Baseline Scores / Withdrawal of emollients / Start of Treatment (topical application of the gel/vehicle)/ Dispensing of medication/ Distribution of Patient’s Dairy Card (PDCs)/Pregnancy monitoring (female patients). Pharmacokinetic (PK) analysis (for selected patients):

• One pre-dose blood sample (5 mL) collection (Prior to gel application)

• After the application of gel, post dose blood sample (5 mL each)

collection at 1 hr, 1.50 hr, 2 hr, 2.50 hr, 3 hr, 4 hr, 6 hr and 10 hrs (in a pre-labelled sample collection tube containing K2EDTA as the anticoagulant) in investigator’s clinic.

Visit 4: Week 4 (Day 28) (+ 2 day window period) – Compliance Check and return of IMP / Efficacy & Safety Assessment / Dispensing of medication/ Distribution of PDCs/Pregnancy monitoring (female patients).

Visit 5: Week 8 (Day 56) (+ 2 day window period) – Compliance Check and return of IMP / Efficacy & Safety Assessment / Dispensing of medication / Distribution of PDCs/Pregnancy monitoring (female patients).

Visit 6: Week 12 (Day 84) (+ 2 day window period)

• Compliance Check and return of IMP

• Efficacy & Safety Assessment.

• PK analysis (for selected patients) will be done prior to morning gel application (pre-dose, 5 mL) and after post dose blood sample (5 mL each) collection at 1 hr, 1.50 hr, 2 hr, 2.50 hr, 3 hr, 4 hr, 6 hr and 10hrs (in a pre-labelled sample collection tube containing K2EDTA as the anti-coagulant) in investigator’s clinic.

Those patients visiting the clinic utilizing + 2 day window period on any visit will become due for the next visit as per the pre-defined visit schedule.

For all patients who discontinue treatment prior to week 12, an unscheduled end of treatment visit is to be performed and last visit values will be included.

|

Sampling Schedule for Drug’s Concentration Assessment in Systemic Circulation

Out of total 311 randomized patients among three treatment arms, some 75 patients (25 patients from each arm) at selected sites will undergo PK assessment. Blood sample (5 mL each) will be collected to measure the systemic exposure of Apremilast on Week 0 and Week 12 at 0 hr (pre dose), 1hr, 1.50 hr, 2 hr, 2.50 hr, 3 hr, 4 hr, 6 hr and 10 hrs after the morning application of the formulation at the investigator’s clinic in a pre-labelled sample collection tube containing K2EDTA as the anticoagulant. Patients undergoing PK assessment to find drug’s presence in systemic circulation will remain in-house at the site on Week 0 and week 12 until the samples are collected.

Total 18 samples per patient (PK analysis)

Volume of blood collection - 05 mL per sample collection.

The blood concentration of Apremilast at 0 hr (pre-dose), 1 hr, 1.50 hr, 2 hr,

2.50 hr, 3 hr, 4 hr, 6 hr and 10 hrs from each patient after post-morning application of gel on Week 0 and Week 12 will be tabulated and descriptive statistics will be computed.

Total Blood Loss = Approx. 90 ml for PK analysis. Approx. 20 ml for screening and post safety assessments. For serum _-HCG test (in case of female only) an extra 4 mL will be collected. Thus, not exceeding 114 mL per patient.

|Sample handling:

After collection, blood sample containing vacutainer will be placed in ice water bath or in any other chilling device till they are placed in refrigerated centrifuge.

Blood samples will be placed in a refrigerated centrifuge immediately  after sample collection and then spun at 4000 ± 100 rpm for 10 minutes at 4ºC ± 2ºC.Plasma obtained from the blood sample will be separated and transferred into two different polypropylene tubes/RIA vials (Aliquot 1of 2 and Aliquot 2 of 2). Each tube/vial will be labeled with Site number, Project No., Patient No., Sampling time point and Aliquot No.

Plasma sample volume allocation:

Aliquot 1 of 2 : 1.5 mL of plasma (approximately)

Aliquot 2 of 2: rest of the plasma.

All samples will be stored at a temperature of -23°C or below for interim storage at the clinical site until transferred on dry ice along with data logger to the bio analytical site after which the sample receipt would be verified for its accountability and storage conditions and will be stored at a temperature of- 70±15°C.

At the end of the study or end of PK sampling visit, aliquot 1 of 2 samples will be transferred for analysis to Bioanalytical facility and aliquot 2 of 2 samples will be transferred only after receipt of acknowledgement of aliquot 1 of 2.

|Bioanalytical Procedure:

The plasma concentration of Apremilast will be analyzed using a Liquid Chromatography Mass Spectrometry (LC-MS/MS) method at the

bioanalytical laboratory of Aizant Drug Research Solutions Pvt. Ltd.,

Hyderabad, which is validated according to the international guidelines.

|Safety Assessment

Safety will be assessed throughout by AE reporting, laboratory testing (hematology, biochemistry, and urinalysis as mentioned in the schedule of activities on specified visits), physical examination, and vital signs.

All pre-treatment AEs (related and unrelated, serious and non-serious) will be recorded in the relevant “Medical Event Form†from the time the informed consent is signed. Adverse Events occurring post treatment (events that occurred after the first dose of medication and up to 14 days post treatment) are to be recorded on the AE forms in the case report form (CRF) and in source documents.

Appearance of newer lesions post randomization will not be captured as AEs. But will be captured separately in CRFs.

Time from first treatment to withdrawal or onset of AE will also be assessed. Where applicable, a diagnosis rather than symptoms should be recorded. If a diagnosis has not been made, then each symptom should be reported individually.

All AEs – irrespective of the suspected causality – will be followed-up as clinically indicated until its resolution or, if non-resolving, until considered stable. Unresolved AEs will be followed-up until resolved/ stabilized, whichever is earlier. Where appropriate, medical tests and examinations will be performed to document resolution of event(s).

|Statistical Methods

Baseline comparability of treatment groups will be evaluated with regards to patient demographics and disease characteristics for homogeneity.

Mean and standard deviations (SD) will be reported for continuous variables. Frequencies and percentages will be reported for categorical variables. ANOVA will be used to compare differences between groups for continuous variables, and Chi-square test or Fisher exact tests will be used to test between group differences for categorical variables. The difference in sPGA, PASI, VAS and DLQI scores of pre-treatment and post treatment will be performed by subtracting the score determined post treatment from the score at baseline. The change in score will be analyzed using Nonparametric Wilcoxon rank sum test.

The 95% confidence limits for difference in mean change from baseline in the above mentioned scores between treatment groups will be computed for the intent-to treat population and per protocol population. Safety analysis will be conducted for the Safety population. Last observation including baseline value will be carried forward for missing observation or drop outs. Fisher’s exact test will be used to compare the incidence of adverse events between the two treatment groups.

The accepted level of significance for all tests will be  = 0.05. All analyses will be performed using appropriate validated software.

|Sample Size and Power

A Total of 311 subjects or patients with mild to moderate psoriasis will be included in the pivotal study.

Pharmacokinetic evaluation would be performed on a smaller group (at least 75 subjects. i.e., 25 patients from each arm) of enrolled patients.

Profile of pharmacokinetics post-dose for Cmax, Area Under Curve, Tmax,

t1/2 will be estimated by using appropriate validated software.

|Study Centre’s

Multi Centre is expected to participate in the study