| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the long-term clinical efficacy and safety of Tazarotene 0.05% cream in LI patients in real-life setting conditions. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are :
- To assess the durability of remission (relapse/prevention) under maintenance treatment.
- To assess the relapse/rebound after the end of the maintenance treatment.
- To evaluate benefit and life quality outcome of the patients.
- To measure the systemic absorption of the active drug in LI patients in the real life condition of product use at the end of initial therapy and maintenance therapy.
- To monitor laboratory values during normal conditions of product use.
- To evaluate the overall acceptability of the product by the patients.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Male or female patients of at least 9 years old,
[For Swedish center only] young girls over 15 years of age,
[For Tunisian centers] patient over 18 years of age,
Patients with a documented diagnosis of LI based on clinical signs, histopathology and/or genotype and, when possible, pedigree analysis,
Patients requiring topical treatment by keratolytics either as monotherapy or as alternate therapy to oral retinoids,
Patients with a global score of at least 3 for each parameter scaling and roughness, according to the scale used for primary efficacy parameter,
Patients or patient’s parents/guardians able to understand and follow the study procedures,
Written informed consent (personally signed and dated) from the patients and/or parent(s)/guardian(s) (according to local legislation),
Patients or patients’ parents/guardians affiliated to a healthcare security system (when applicable in the national regulation).
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| E.4 | Principal exclusion criteria |
Patients under 9 years of age,
[For Swedish center only] young girls under 15 years of age,
[For Tunisian centers] patient under 18 years of age,
Pregnant or lactating women,
Women of childbearing potential with no reliable medical contraception (oral contraceptive, intra-uterine contraceptive device), and unwilling to use condoms up to 8 weeks after the last test product application,
[For german centers only] Young girls (9-17 years old) who are already of child bearing potential but not already taking a medical contraception (oral contraceptive, intra uterine contraceptive device) beforehand to the clinical trial, and unwilling to use condoms up to 8 weeks after the last test product application,
Women of childbearing potential with a positive systemic pregnancy test at baseline,
Patients with congenital ichthyoses other than LI,
Patients with an erythrodermic component of LI (EARLI),
Patients with LI of overall severity < 3 for scaling or roughness, according to the scale used for primary efficacy parameter,
Patients with lesional superinfection,
Patients with skin or other disease likely to interfere with the study conduct or the evaluation parameters,
Patients with excessive pruritus, burning, skin redness or peeling, not fully recovered at baseline,
Patients with inherent sensitivity to sunlight,
Patients with a known contact allergy to one of the ingredients contained in the test products,
Patients treated with topicals (e.g. vitamin A analogues, vitamin D analogues) within 14 days prior to baseline,
Patients treated with tazarotene gel within 28 days prior to baseline,
Patients treated with keratolytics (e.g. urea, hydroxy-acids) or moisturizers other than the standard moisturizer within 7 days prior to baseline,
Patients treated with concomitant dermatologic medications and cosmetics that have a strong drying effect within 7 days prior to baseline,
Patients treated with oral retinoids during the preceding 28 days, or with oral vitamin A supplementation (more than 3000 IU per day) during the preceding 7 days of baseline,
Patients treated with drugs known to be photosensitizers (e.g. oral and topical antiinflammatories, thiazides, tetracyclines, quinolones, phenothiazines, sulfonamides, hydrochlorates, chlorpromazine, psoralen, amiodarone, tar) within 14 days prior to baseline,
Patients with a medical condition that potentially alters bone metabolism (e.g. osteoporosis, thyroid dysfuntion, Cushing syndrome) or treated with a medication interfering with bone activity (e.g. corticosteroids, thyroid hormones, vitamin D analogues, cytotoxics, biphospbonates, calcitonins, tetracyclines, quinolones, thiazides, salicylates in long-term course, heparin, theophylline, barbiturates, colchicines) within the preceding 56 days prior to baseline,
Patients treated with UV therapy or patients medically exposed to UV within 28 days prior to baseline,
Patients having significant sun exposure due to their occupation,
Patients who participated in a study within the 3 months prior to study entry,
Patients or patients’ parents/guardians who are unable to understand and/or to follow the study procedures and patient instructions,
Patients or patients’ parents/guardians who are unwilling to give personally signed and dated written informed consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Response to test treatment at the end of initial therapy (Day 84)
At each study visit, the overall severity of scaling (visual assessment) and roughness (palpation) will be evaluated by an independent physician not involved in the management of the patients (masked assessment), according to the following 5-point Physician General Assessment (PGA) scale:
0 = Normal skin all over the treated BSA
1 = Lesions of slight intensity involving < 30% of the treated BSA
2 = Lesions of slight intensity involving > 30% of the treated BSA
3 = Lesions of moderate intensity involving > 30% of the treated BSA
4 = Lesions of severe intensity involving > 30% of the treated BSA
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| E.5.2 | Secondary end point(s) |
Time-course severity of scaling, roughness and erythema on the treated areas, according to the scale used in the primary efficacy parameter for scaling and roughness and to a 4-point severity scale for erythema (0 = normal skin color, 1 = barely detectable pink color, 2 = definite red hue, 3 = intense red color) at Baseline, Days 28, 56, 84, 126, 168, 196, and 224 visits, by the independent physician.
Assessment of the relapse/rebound of the treated areas, according to the scale defined in the primary efficacy parameter, during Period II and Period III. A relapse will be defined as a severity score of at least 3 for scaling or roughness. A rebound will be defined as a score over the baseline score on scaling or roughness.
Separate assessment of the overall clinical severity of the lesions on palms and soles at Baseline, Days 28, 56, 84, 126, 168, 196 and 224 visits, according to a 4-point severity scale (0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe), by the independent physician.
Autoevaluation of the overall severity of the lesions by the patients, at all study visits from Baseline. Autoevaluation tools will be a 10-cm visual analogue scale filled in by the patients themselves for adults and children of at least 12 years of age, and by the parents for children below 12 years of age.
Life quality assessment by the patients, using the generic Short-Form 12 questionnaire (SF-12) for patients from 16 years of age and the Dermatologic Life Quality Index (DLQI) for patients over 16 years of age (i.e. from 17 years of age), or the child DLQI (CDLQI) for patients between 9 years and 16 years old, at Baseline, Day 84 (end of Period I) and Day 168 (end of Period II).
Global local tolerance made on Day 84 (end of Period I) and Day 168 (end of Period II), according to the following 4-point scale,
1 = Very good tolerance: no subjective or physical sign of local side effects.
2 = Good tolerance: transitory subjective signs, without physical sign nor necessary modification of the frequency of test product application.
3 = Poor tolerance : persisting subjective signs or physical signs of local side effects, leading to modification of the frequency of the test product application but no treatment discontinuation.
4 = Very poor tolerance: subjective and/or physical signs leading to treatment discontinuation.
Overall acceptability by the patients (efficacy, local tolerance, ease of use) on Day 84 (end of Period I) and end of Period II (Day 168). Patients (or parents for children < 12 years old) will be asked to quote each acceptability parameter according to the 4-point scale that follows:
0 = Not satisfactory at all
1 = Poorly satisfactory
2 = Satisfactory
3 = Very satisfactory
Plasma monitoring of Tazarotenic acid at baseline, Day 84 (end of Period I),Day 168 (end of Period II), Day 224 (end of period III). Additional measurement will be performed 6 months and 12 months after study end in the paediatric population, through an observational period providing that the value at study end will be measured above the limit of quantification.
Blood laboratory tests (hematology, chemistry, liver activity markers, serum lipids) at Baseline, Day 84 (end of Period I), Day 168 (end of Period II), and Day 224 (end of period III), Clinically significant abnormal values will be recorded as adverse event and followed-up. Additional measurement will be performed 6 months and 12 months after study end in the paediatric population, through an observational period.
Measurement of bone metabolism, using plasmatic biochemical markers (osteocalcin, CTX, PTH, calcemia, alcalin phosphatase, phosphoremia) at Baseline, Day 84 (end of Period I), Day 168 (end of Period II), and Day 224 (end of period III). Additional measurement will be performed 6 months and 12 months after study end in the paediatric population, through an observational period.
Physical examination at each visit.
Adverse events. An independent Data Safety Management Board (DSMB) will be set up to review adverse events during the study and take any decision in the interest of the patient safety.
Compliance (records of application frequency, returned tubes weighing).
Period IV: All the parameters assessed at the D168 visit of the initial study will be collected at 3-monthly intervals.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 1 year children follow up and study extension open labelled (Period IV) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Urea 10% for adult or 5% for children |
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| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of the initial study: The end of the initial study is the date of the last visit of the last patient of the Period II or Period III. End of the children follow-up: The end of the paediatric follow-up is the date of the last visit of the last child undergoing the follow-up.
End of the Study extension/Period IV: The end of the study extension/Period IV is the date of the last visit of the last patient undergoing the study extension.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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