| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recalcitrant acne vulgaris |
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| E.1.1.1 | Medical condition in easily understood language |
| common acne not responding to standard treatment |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000519 |
| E.1.2 | Term | Acne vulgaris |
| E.1.2 | System Organ Class | 100000004858 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of the nacystelyn in combination with isotretinoin of different concentrations in patients with recalcitrant acne vulgaris |
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| E.2.2 | Secondary objectives of the trial |
| To assess the efficacy, the safety and the tolerability of the study treatments |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must satisfy the following criteria before entering the study:
1.Males or females, aged between 12 and 50 years, inclusively.
2.Patients presenting a severe recalcitrant acne vulgaris with 10 or more inflammatory nodules with a diameter of 5 mm or greater (facial and/or truncal).
3.Weight between 40 – 110 kg.
4.Able to comply with all study procedures.
5.Patients who are willing and able to provide written informed consent, after being informed of all the pertinent aspects of the study.
If the patient is female and of childbearing potential, she must be using two separate and efficient means of birth control. (See “contraception and pregnancy tests section for more details). Contraception should be used for at least 1 month prior to starting treatments, throughout treatments and continue for at least 1 month after stopping treatments. A negative pregnancy test must be provided at screening and within 11 days prior to initiating therapy or the day of the randomisation at the latest. Even female patients who normally do not employ contraception due to a history of infertility, amenorrhea or claim absence of sexual activity will have to use contraception while taking the study treatments
Note: A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from participating in the study:
1.Evidence of any clinically significant immunological, neoplastic, endocrine, hematological, gastrointestinal, neurological, cardiovascular, or psychiatric abnormalities.
2.Abnormal liver function (hepatocellular insufficiency, chronic or active liver disease, biliary tract disease, sustained elevation of serum liver enzymes (simultaneously ASAT and ALAT > 2x UNL)).
3.Abnormal renal function (clearance of creatinine < 50 mL/min and creatinemia > 20 mg/L) or any renal disease likely to lead to renal dysfunctions.
4.No clinically significant abnormal laboratory value and/or vital signs measurement as per the judgement of the study investigator.
5.Patients with any sensitivity or allergy to any of the products used within this clinical trial: known hypersensitivity to isotretinoin, retinoic acid and derivatives of vitamin A.
6.Any skin disease that might interfere with the evaluation of severe recalcitrant nodular acne.
7.Patients with a history or current psychiatric illness (e.g. depression, psychotic symptoms, suicidal behavior).
8.Patients who, during the past month, have received systemic corticosteroids and during the past 7 days have received topical corticosteroids. For isotretinoin 6 months wash out period should be fulfilled.
9.Recent history of alcoholism (above 21 beverages per week. One alcoholic beverage is defined as 30 mL distilled spirits, 120 mL wine, or 330 mL beer) or drug abuse.
10.Use of any prohibited medication as detailed in the concomitant medication section of the protocol.
11.Use of any investigational drug or participation in any clinical trial within 3 months of their first dosing.
12.Donation of blood during the study and for one month after discontinuation of study treatment.
13.Pregnant and breastfeeding women
14.Subjects who were unlikely to co-operate with the requirements of the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The main study hypothesis is that Test 2 is non-inferior to Reference on the relative change in the number of facial and truncal nodules between W0 and W20
A mixed model for repeated measures with baseline value, group, time and interaction group*time as fixed factors will be built. The natural logarithm of the relative change from baseline will be regressed over time (W4, W8, W12, W16, W20). All timepoints will be included into the model for taking into account the variability of all timepoint measures. Several covariance structure of the matrix will be tested (UN, AR(1), TOEPH, VC). The matrix will be selected according to the Akaike information criterion (AIC). The preferred model is the one with the minimum AIC value.
Interaction group*time will be kept in the model even if not significant. A simple effect of groups on the change from W0 to W20 will be assessed at W20 using a test of slice effect using this mixed model. Contrast between Test 2 and Reference will be calculated at W20 and will be expressed along with a 95% two-sided confidence interval after exponentiation. If the ratio Test 2 / Reference is > 0.85, test 2 will be considered non-inferior to Reference. No adjustment of Type 1 error risk will be made.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
All endpoints involving relative changes from baseline over time will be analyzed as the primary endpoint unless the comparison to a non-inferiority threshold. A slice effect will be tested at each time point. For the comparison of Test 1 and Reference on the relative change in the number of nodules between W0 and W8, no adjustment of Type 1 error rate will be made. For other comparisons involving Test 1 vs Reference and Test 2 vs Reference a Dunnett’s adjustment will be made.
End points involving absolute changes from baseline over time will be analyzed as follows. A mixed model for repeated measures with baseline value, group, time and interaction group*time as fixed factors will be built. The absolute change from baseline will be regressed over time (W4, W8, W12, W16, W20). All timepoints will be included into the model for taking into account the variability of all timepoint measures. Several covariance structure of the matrix will be tested (UN, AR(1), TOEPH, VC). The matrix will be selected according to the Akaike information criterion (AIC). The preferred model is the one with the minimum AIC value.
Interaction group*time will be kept in the model even if not significant. A test of slice effect will be performed at each time point using this mixed model. Contrasts between Test 1 and reference and between Test 2 and Reference will be calculated at each time point and will be expressed along with a 95% two-sided confidence interval with a Dunnett’s adjustment.
The percentage of patients with a 90% clearance of the nodules will be estimated at each time point (W2, W4, W8, W12, W16, W20) using the Kaplan-Meier method. Estimates will be calculated at each time point along with a 95% two-sided confidence interval. The same method will apply for the percentage of patients with PGSA 0 or 1, and for the percentage of patients with PAE 0 or 1. Groups will be compared by the log rank test.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability of the study treatments |
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| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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