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    EudraCT Number:2018-000261-36
    Sponsor's Protocol Code Number:HTA-HG5-02
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-07
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000261-36
    A.3Full title of the trial
    Studio clinico multicentrico, in aperto, non controllato, per confermare l'efficacia e la sicurezza di lembi epidermici autologhi coltivati su supporto di fibrina contenenti cellule staminali epidermiche geneticamente modificate per il ripristino dell'epidermide in pazienti con Epidermolisi Bollosa Giunzionale (HOLOGENE 5)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene Therapy for patient with Junctional Epidermolysis Bullosa
    terapia genica per pazienti affetti da Epidrmolisi Bullosa Giunzionale
    A.3.2Name or abbreviated title of the trial where available
    Hologene 5
    Hologene 5
    A.4.1Sponsor's protocol code numberHTA-HG5-02
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHolostem Terapie Avanzate s.r.l.
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCROSS Research SA
    B.5.2Functional name of contact pointClinical Project Leader
    B.5.3 Address:
    B.5.3.1Street AddressVia FA Giorgioli 14
    B.5.3.2Town/ cityArzo
    B.5.3.3Post code6864
    B.5.4Telephone number+419163005120
    B.5.5Fax number+41916300511
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU73/15/1465
    D.3 Description of the IMP
    D.3.1Product nameHologene 5
    D.3.2Product code [Hologene 5 DS]
    D.3.4Pharmaceutical form Implant
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codehologene 5 DS
    D.3.9.3Other descriptive nameEx-vivo expanded autologous human keratinocytes suspension containing epidermal stem cells genetically modified with a gamma-retroviral (rv) vector expressing the full-length LAMB3 cDNA.
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D. cell therapy medicinal product No
    D. therapy medical product Yes
    D. Engineered Product Yes
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Inherited Epidermolysis Bullosa (EB) is a group of rare, devastating genetic disorders characterized by structural and mechanical fragility of
    skin and mucosal membranes, impairing the patient's quality of life. Generalized JEB is a chronic, life-threatening condition caused by
    mutations in genes– encoding different chains of laminin 332. All of these mutations hamper hemidesmosome formation, causing blisters. The most frequent, and perhaps most severe, JEB is due to mutations in LAMB3.
    L’epidermolisi bollosa ereditaria è una rara malattia genetica caratterizzata da fragilità strutturale e meccanica della pelle. Ciò è causato da variazioni in determinati geni che possono rendere difettose le proteine strutturali della pelle, in particolare degli strati più superficiali (epidermide). La epidermolisi bullosa giunzionale il difetto è a livello della proteina lamina 332 importante per stabilizzare i desmosomi, strutture che fanno da attacco tra epidermide e derma.
    E.1.1.1Medical condition in easily understood language
    Gene Therapy for patient with Junctional Epidermolysis Bullosa
    Terapia Genica per pazienti affetti da Epidermolisi Bullosa Giunzionale
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014989
    E.1.2Term Epidermolysis bullosa
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective
    To evaluate the efficacy of HOLOGENE 5 at 12 months follow-up as percentage of success based on the following assessments:
    • clinical performance as % of re-epithelization in the absence of blisters measured by Investigator through a software named Holosnapp;
    • functional evaluation based on laboratory analyses and mechanical assessment;
    • patient outcome assessment based on patients’ improvement perception on the transplanted areas.
    Valutazione dell’efficacia di Hologene 5 a 12 mesi dal trapianto come percentuale di successo sulla base delle seguenti valutazioni:
    • clinica come % di ri-epitelizzazione in assenza di vesciche misurate dallo sperimentatore attraverso un software chiamato Holosnapp;
    • funzionale sulla base di analisi di laboratorio e valutazione meccanica;
    • risultato da parte del paziente sulla base della percezione del miglioramento dei pazienti sulle aree trapiantate.
    E.2.2Secondary objectives of the trial
    Secondary Objectives
    efficacy as % of re-epithelization measured through Holosnapp by Independent Assessor at 12 months (m) follow-up;
    efficacy as % of re-epithelization measured through Holosnapp by Investigator;
    efficacy as Investigator judgment based on engraftment, erosions, infection, appearance of the skin, functionality, etc. at 1, 3, 6, 9 and 12 m;
    To evaluate the dermal/epidermal junction using (OCT) at 12 m follow-up;
    change in Quality of Treated Area(s) from baseline, based on EBDASI at 12 m follow-up;
    To evaluate the safety of the treatment .
    Exploratory Objectives
    To evaluate potential immune reactions;
    To evaluate change in Quality of Treated Area(s) from baseline based on the questionnaires in ‘HoloApp’;
    percentage of patients with one or more transplantation scored as successes ;
    To evaluate efficacy as intra-patient treatment comparison based on the efficacy parameters,
    To evaluate improvement of patient’s quality of life through QOLEB.
    Obiettivi secondari e esplorativi
    Valutazione dell’efficacia come % di ri-epitelizzazione da un valutatore indipendente 12 mesi dopo il trapianto;
    Valutazione dell’efficacia come % di ri-epitelizzazione misurata attraverso Holosnapp;
    Valutazione dell’efficacia come giudizio dello sperimentatore basato su attecchimento, erosioni, infezione, ecc. a 1, 3, 6, 9 e 12 mesi;
    Valutazione dell’integrità strutturale della giunzione dermo/epidermica attraverso OCT a 12 mesi;
    Valutazione del cambiamento della qualità delle aree trattate rispetto al basale basato sull’EBDASI a 12 mesi.
    Valutazione della sicurezza del trattamento.
    Valutazione delle reazioni immunitarie al transgene;
    Valutazione del cambiamento della qualità delle aree trattate sulla base dei questionari in HoloApp;
    Valutazione dell’efficacia definita come percentuale di pazienti che hanno effettuato uno o più trapianti riportati come successi (regola dei due passaggi) a 12 mesi dal trattamento;
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria:
    1. Signed and dated informed consent prior to any study-related procedures;
    2. Male and female patients between 6-month-old and 55-year-old;
    3. Diagnosis of generalized intermediate LAMB3-dependent JEB, confirmed by NGS or Sanger sequencing and immunofluorescence;
    4. Detectable residual expression of laminin 332 (and its beta3 chain) by immunofluorescence and/or Western analysis;
    5. Presence of blisters and/or = 10 cm2 erosions (persistent or recurrent for more than 3 months);
    6. A cooperative attitude to follow the study procedures (caregivers in case of children);
    7. Patients’ compliance with the study schedule and procedures, including complete immobilization of the transplanted areas for at least two weeks and hospitalization up to 1 month after transplantation.
    I pazienti devono soddisfare tutti i seguenti criteri di inclusione:
    1. Consenso informato firmato e datato prima di qualsiasi procedura relativa allo studio;
    2. Pazienti maschi e femmine di età compresa tra 6 mesi e 55 anni;
    3. Diagnosi di Epidermolisi Bollosa Giunzionale (JEB) intermedia generalizzata dovuta a mutazione del gene LAMB3, confermato da sequenziamento e immunofluorescenza attraverso NGS o Sanger;
    4. Espressione residua rilevabile della laminina 332 (e della sua catena beta3) mediante immunofluorescenza e/o analisi western blot;
    5. Presenza di vesciche e/o erosioni da =10 cm2 (persistente o ricorrente per più di 3 mesi);
    6. Un atteggiamento cooperativo per seguire le procedure di studio (assistenza in caso di bambini);
    7. Conformità dei pazienti con il programma e le procedure dello studio, compresa l'immobilizzazione completa delle aree trapiantate per almeno due settimane e il ricovero in ospedale fino a 1 mese dopo il trapianto.
    E.4Principal exclusion criteria
    Patients must not meet all of the following exclusion criteria:
    1. Known or suspected intolerance to anaesthesia;
    2. Bad general condition (ECOG index >1);
    3. Presence of Squamous Cell Carcinomas (SCCs) in the area(s) qualified for treatment;
    4. Clinical and/or laboratory signs of acute systemic infections at the time of screening. Patient can be re-screened after appropriate treatment;
    5. Female subjects: pregnant or lactating women and all women with childbearing potential unless they are willing to use one or more reliable methods of contraception with a Pearl index =1. Reliable contraception should be maintained throughout the study.
    A pregnancy test will be performed at screening in all women of childbearing potential and repeated before biopsy treatment and at all visits. A pregnancy test will not be required for post-menopausal women (physiologic menopause defined as “12 consecutive months of amenorrhea”) or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy).
    Parental control will be applied for the pediatric population when needed;
    6. Allergy, sensitivity or intolerance to study medication excipients or other material required by study protocol (as per Investigator’s brochure):
    - Transport medium (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine)
    - Fibrin support
    - Povidone iodine or Prontosan® (or equivalent selected for the treatment in consultation with the Sponsor Medical Expert)
    7. Contraindications to the local or systemic antibiotics and/or corticosteroids foreseen by the protocol;
    8. Contraindications to undergo extensive surgical procedures;
    9. Presence of i) systemic diseases, ii) clinically significant or unstable concurrent disease, iii) other concomitant medical conditions, iv) other clinical contraindications to stem cell transplantation, which based on Investigator’s judgment, in consultation with the Sponsor Medical Expert may affect the participation in the study or the grafting procedure;
    10. Patients (or parents in case of paediatric subject) unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study procedures and treatments.
    11. Previous treatments or participation in clinical trials envisaging the use of cells (including bone marrow transplantation, BMT) and/or both in vivo or ex vivo gene therapy products.
    I pazienti non devono soddisfare tutti i seguenti criteri di esclusione:
    1. Intolleranza nota o sospetta all'anestesia;
    2. Cattive condizioni generali (indice ECOG> 1);
    3. Presenza di carcinomi a cellule squamose (SCC) nelle aree qualificate per il trattamento;
    4. Segni clinici e/o di laboratorio di infezioni sistemiche acute al momento dello screening. Il paziente può essere riesaminato dopo il trattamento appropriato;
    5. Soggetti femminili: donne in gravidanza o in allattamento e tutte le donne in età fertile, a meno che non siano disposte a utilizzare uno o più metodi contraccettivi affidabili con un indice di Pearl =1. La contraccezione affidabile deve essere mantenuta per tutto lo studio.
    Un test di gravidanza verrà eseguito allo screening in tutte le donne in età fertile e ripetuto prima del trattamento con biopsia e in tutte le visite. Non sarà richiesto un test di gravidanza per le donne in post-menopausa (menopausa fisiologica definita come "12 mesi consecutivi di amenorrea”) o per le donne fertili che si siano sottoposte a metodi contraccettivi chirurgici in modo permanente (ad es. occlusione tubarica, isterectomia o salpingectomia bilaterale).
    Il controllo parentale sarà applicato per la popolazione pediatrica quando necessario;
    6. Allergia, sensibilità o intolleranza agli eccipienti del farmaco in studio o altri prodotti previsti dal protocollo di studio (secondo il documento’ Informazioni per lo sperimentatore):
    - Mezzo di trasporto (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine))
    - Supporto di fibrina
    - Povidone iodio o Prontosan® (o equivalente selezionato per il trattamento in consultazione con lo sponsor medico esperto)
    7. Controindicazioni agli antibiotici locali o sistemici e/o ai corticosteroidi previsti dal protocollo;
    8. Controindicazioni per sottoporsi a estese procedure chirurgiche;
    9. Presenza di i) patologie sistemiche, ii) patologie concomitanti clinicamente significative o instabili, iii) altre condizioni mediche concomitanti, iv) altre controindicazioni cliniche al trapianto di cellule staminali, che sulla base del giudizio dell'esaminatore, in consultazione con lo sponsor medico esperto possono influenzare la partecipazione nello studio o nella procedura di innesto;
    10. I pazienti (o i genitori in caso di soggetto pediatrico) non possono rispettare il protocollo di studio o non siano in grado di comprendere la natura e la portata dello studio o i possibili benefici o gli effetti indesiderati delle procedure e dei trattamenti dello studio.
    11. Trattamenti precedenti o partecipazione a studi clinici che prevedevano l'uso di cellule (incluso trapianto di midollo osseo, BMT) e/o di entrambi i prodotti di terapia genica in vivo o ex vivo.
    E.5 End points
    E.5.1Primary end point(s)
    • Percentage of transplantation scored as success at 12 months follow-up based on the definition of success using the 2-steps rule
    • Percentuale di trapianti giudicate come successo dopo 12 mesi dal trattamento sulla base la regola dei due passaggi.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months
    12 mesi
    E.5.2Secondary end point(s)
    • Percentage of transplantation success at 12 months follow-up as % of re-epithelization measured through Holosnapp by the Independent Assessor;
    • Percentage of transplantation success at 1, 3, 6, 9 and 12 months follow-up as % of re-epithelization measured through Holosnapp by the Investigator;
    • Percentage of transplantation success at 1, 3, 6, 9 and 12 months follow-up through Investigator judgment based on engraftment, erosions, infection, aspects, functionality, etc.;
    • Percentage of normal and abnormal NCS (abnormal, Not Clinically Significant) Optical Coherence Tomography (OCT) at 12 months follow-up;
    • Change in Quality of Treated Areas from baseline at 12 months follow-up, based on EBDASI;
    • Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and ADRs;
    • Vital signs and laboratory results
    • Percentuale di successi del trapianto a 12 mesi dal trattamento come percentuale di ri-epitelizzazione misurata attraverso Holosnapp dal valutatore indipendente;
    • Percentuale di successi del trapianto a 1, 3, 6, 9 e 12 mesi dal trattamento come percentuale di ri-epitelizzazione misurata tramite Holosnapp dallo sperimentatore;
    • Percentuale di successi del trapianto a 1, 3, 6, 9 e 12 mesi dal trattamento attraverso il giudizio dello sperimentatore basato su attecchimento, erosioni, infezione, aspetti, funzionalità, ecc.;
    • Percentuale di valori normali o anormali NCS (anormali, non clinicamente significativi) di Tomografia Ottica a Coerenza (OCT) 12 mesi dopo il trapianto;
    • Cambiamenti nella qualità delle aree trattate dal basale a 12 mesi dal trapianto, basato su EBDASI;
    • Eventi avversi emergenti dal trattamento (TEAE), eventi avversi seri (SAE) e reazioni avverse al farmaco (ADR);
    • Segni vitali e risultati dei parametri di laboratorio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 3, 6, 9 and 12 months
    1, 3, 6, 9 e 12 mesi
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    studio multicentrico, prospettico, non controllato, interventistico e pivotale
    multicentric, prospective, uncontrolled, interventional, pivotal clinical trial.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F. of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 6
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the study, patient will be asked to partecipate to an Observational
    A fine studio ai pazienti sarà chiesto di partecipare a uno studio Osservazionale per essere seguiti
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-07
    P. End of Trial
    P.End of Trial StatusOngoing
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