Efficacy of an Adapted Antibiotherapy in Hurley Stage 2 Hidradenitis Suppurativa Patients

Study Overview
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Brief Summary
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The study evaluates the efficacy of an adapted antibiotherapy in Hurley stage 2 active Hidradenitis Suppurativa patients versus tetracycline derivative

Detailed Description
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The antibiotic strategy is targeted against specific pathobionts which have been identified in HS lesions by the investigator's team. Half of participants will receive a 3-week course of ceftriaxone + metronidazole treatment followed by 3 weeks of rifampicin + moxifloxacin + metronidazole combination, then 6 weeks of rifampin + moxifloxacin (experimental groupe), versus a 12 weeks course of lymecycline (control group) Double blind treatment phase will stop at week 12. All patients whatever their randomization arm or their remission status will begin follow-up treatment according to standard care recommendations (Société Française de Dermatologie): lymecycline, doxycycline or cotrimoxazole. Prescription will be upon decision of the investigator. This maintenance treatment is not experimental.

Official Title
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A Multicentric Randomized Double-Blind Phase 3 Trial Evaluating the Efficacy of an Adapted Antibiotherapy in Hurley Stage 2 Active Hidradenitis Suppurativa Patients Versus Tetracycline Derivative

Conditions
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Hidradenitis Suppurativa

Intervention / Treatment
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* Drug: ROCEPHIN, metronidazole, RIFADIN, IZILOX, placebo combination therapy
* Drug: Lymecyclin and corresponding placebos of the experimental arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults < 60 years old Diagnosis of HS according to European Dermatology guidelines: Recurrent inflammation occurring more than 2 times in the past 6 months in the inverse regions of the body, presenting with nodules, sinus-tracts and/or scarring. Signs: Involvement of axilla, genitofemoral area, perineum, gluteal area (and infra-mammary areafor women). Presence of nodules (inflamed or noninflamed), sinus tracts (inflamed or noninflamed), abscesses, scarring (atrophic, mesh-like, red, hypertrophic or linear) Active HS with i) ≥ 1 year of evolution and ii) ≥ 4 flares during the previous year Clinical severity of HS at inclusion: Hurley stage 2 BMI < 35 Written informed consent from patient Patient able to complete DLQI Patients affiliated to the French health system (Assurance Maladie), except French state medical aid beneficiaries (Aide Médicale d'Etat) Active compatible contraception for men and women of childbearing or inability to procreate Available laboratory blood test performed within the last 2-months Non inclusion Criteria: Person < 18 and ≥ 60 years old Former stage 3 HS Previous use of the experimental treatment Unauthorized drugs for the study during the month preceding the inclusion Any contra-indication to study treatments or excipient (e.g. lactose, cornstarch, riboflavin notably): pregnancy, breastfeeding, known allergy to experimental or reference drugs, wheat allergy, tendinopathy, QT prolongation, bradycardia, heart failure, heart rhythm disturbances, hydroelectrolytic disorders, hypokalemia, coagulation disorders, severe liver/kidney dysfunction, porphyria, mandatory use of nonsteroidal anti-inflammatory drugs (NSAIDs) for other medical conditions Unbalanced diabetes (ie HbA1c above 7%) Dysphagia, untreated gastro-oesophageal reflux/ulcer BMI ≥ 35 Immune suppression, inflammatory disease, including gastroenterologic and rheumatologic inflammatory conditions Lactase deficiency, lactose and galactose intolerance Malabsorption syndrome Person living in the same household as another patient Person under guardianship or curatorship Individuals with any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives (e.g patient unable to complete DLQI, or poor predictable observance Participation in another interventional research on health products studies Patients requiring repeated (more than 3/year) use of antibiotics for a chronic disease other than HS Alcohol-dependant patients defined as an addiction to alcohol with a negative impact on health, social or personal life Exclusion criteria: Pregnancy QT prolongation Abnormal result of routine lab tests corresponding to contra-indication to study treatments Unauthorized drug for the study during all the study (from study treatments interactions listed in the SmPC, Cf. unauthorized drug listed in non-inclusion criteria). Development of hypersensitivity to any of the study products and/or excipients (e.g. lactose, corn starch, riboflavin).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentric randomized double-blind phase 3 trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental treatment<br>a 3-week course of ceftriaxone (Rocephin) IV injection (daily dose 2g/day) + oral metronidazole (daily dose 1500mg) followed by a 3-week course of oral rifampicin (Rifadin with 10mg/kg/day) + moxifloxacin (Izilox daily dose 400mg) + metronidazole (daily dose 1500mg) followed by a 6-week course of oral rifampicin (Rifadin with 10mg/kg/day) + moxifloxacin (Izilox daily dose 400mg). A placebo for lymecycline will also be administered during this intensive treatment phase | Drug: ROCEPHIN, metronidazole, RIFADIN, IZILOX, placebo combination therapy<br>* a 3-week course of ceftriaxone injection + oral metronidazole followed by a 3-week course of oral rifampicin + moxifloxacin +metronidazole followed by a 6-week course of oral rifampicin + moxifloxacin<br>* Other names: Experimental treatment;|
| Active Comparator: Control<br>12-week course of oral lymecycline (Tetralysal daily dose 452mg) Placebos for all experimental drugs will also be administered during this intensive treatment phase | Drug: Lymecyclin and corresponding placebos of the experimental arm<br>* 12-week course of oral lymecycline.<br>* Other names: Control treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients reaching clinical remission at week 12, defined by an improvement of 90% of the IHS4 score from the baseline (IHS4 (1)) | The clinical remission is defined as a 90% improvement of the International Hidradenitis Suppurativa Severity Score (IHS4) at week 12 compared to the baseline. The IHS4 score is a validated composite score developped to assess dynamically HS severity (1). It is calculated by adding the number of inflammatory nodules to the number of abscesses multiplied by 2 and to the number of draining tunnels multiplied by 4. A total score of 3 or less corresponds to mild severity HS, 4-10 to moderate severity HS and 11 or higher to severe disease. | at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Physician Global Assessment (PGA) | Physician assessment describe by differents severity : from Clear (no nodule) to Very severe (more than 5 abscesses or fistulas) Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change in Modified Sartorius score | Score calculated by points from 0 (better) with differents parameters involved such as location / number / size / type of lesions Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change in Hurley Score | Score described with 3 stages from I (less severity) to III (most severe) Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change in Hidradenitis Suppurativa Severity Score (IHS4) score | Score calculated by points from <3pts (Mild) to > 11pts (Severe) by nb of nodules, nb of abscesses and nb of draining tunnels Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change in Hidradenitis Suppurativa Clinical Response (HiSCR) score | Global Assessment score of clear, minimal, or mild evaluated by (i) at least a 50% reduction in AN (abscess and nodule count), (ii) no increase in the number of abscesses and (iii) no increase in the number of draining fistulas from baseline Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change in Dermatology Life Quality Index (DLQI) score (Patient's HS evaluation) | Evaluated with the Dermatology Life Quality Index (DLQI) Score calculated by points from 0 to 30 following patient answers on quality of life questions Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Change of patient pain | Intensity of pain evaluated with the visual analog scale (VAS) from 0 (no pain) to 10 (pain as bad as it could possible be) Score evaluated at baseline / week 6 / week 12/ week 24/ week 52 | from baseline to week 52 | 
| Microbiological bacterial Change on the worst lesion microbiome at W12 | By identification of microbiology bacterial metagenomics (by skin lesional swab sample) | at baseline and week 12 | 
| Microbiological metagenomics Change on the worst lesion microbiome at W12 | By identification of multidrug resistant bacteria (by rectal swab sample) | at baseline and week 12 | 
| Number of pain killers received by patients | Number of pain killers prescribed for flares (acute worsening of one or more HS lesions) | from baseline to week 52 | 
| Number of antibiotic treatments received by patients | Number of antibiotic treatments prescribed for flares (acute worsening of one or more HS lesions) | from baseline to week 52 | 
| Time without flare of HS | Evaluated by number of flares reported or not using a patient journal | from baseline to week 52 | 
| Change in BMI | Calculated by combined weight and height measures | from baseline to week 52 | 
| Abnormal biological value of Hemoglobin | measured in g/L, compared to normal ranges | from baseline to week 12 | 
| Abnormal biological value of white cells | measured in units of cells / mm3 , compared to normal ranges | from baseline to week 12 | 
| Abnormal biological value of neutrophils | measured in units of cells / mm3 , compared to normal ranges | from baseline to week 12 | 
| Abnormal biological value of platelet count | measured in units of cells / mm3 , compared to normal ranges | from baseline to week 12 | 
| Abnormal value of AST liver enzyme | AST value > 4 x Upper limit of normal | from baseline to week 12 | 
| Abnormal value of ALT liver enzyme | ALT value > 4 x Upper limit of normal | from baseline to week 12 | 
| Number of adverse events of all kind | AE defined by SOC and PT according to MedDra dictonnary | from baseline to week 52 | 
| Non complete drug administration | Evaluated by total number of capsules not taken according to patient journal | from baseline to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hidradenitis Suppurativa, Antibioresistance, Antibiotherapy