Reasons and aims of the amendment: A) An exclusion criterion, according to which, if a subject have an alcohol concentration of more than 0.8 g/L, he/she is not eligible, is added to the study protocol. In addition, the intake of alcohol during the study will cause the discontinuation of the treatment and the study. Therefore, it is introduced an evaluation by breathalyzer at screening visit and at all subsequent visits. B) According to the protocol, during the treatment phase (10 or 12 days, depending on the detox group), the patient undergo to daily visits at the clinical center, to monitor health status, evaluate abstinence and to dispense daily lofexidine treatment. Recently, it was found that many centers cannot offer assistance on holidays; therefore, they are not able to maintain the schedule of visits planned on weekends or during holidays. This amendment has the aim to adapt the protocol of the study to the real possibility of drug-addicted patient management at the centers. After this amendment, one/two visits during the active treatment could be considered as "optional" rather than "mandatory". The study drug needed to cover these days will dispensed to the patient, with appropriate indications and dosage recommendations. C) To specify in more detail the management of concomitant therapies during the study. To ensure the quality of the results obtained from the treatment with lofexidine and for safety reasons the study protocol excluded the administration of any type of drug during the active treatment phase. Should it be necessary, however, to give the patient a concomitant therapy, the Investigator should consult the Study Coordinator and the Sponsor, to evaluate the need to stop treatment with lofexidine and the participation of the patient in the study. D) To give more guidance on drug management at the end of the study. E) On this occasion, some typos correct were corrected.

Change of principal investigator in a clinical center: The Principal Investigator Laura Tidone was replaced By Paolo Donadoni at the clinical center “A.S.L. Bergamo - Dipartimento delle Dipendenze“, Bergamo (Italy)

Reasons and aims of the amendment: A) The chest radiological examination planned during the Screening visit (day -21 → -7) is eliminated. The decision to remove it is mainly motivated by the fact that this type of examination is not required to assess patient’s eligibility and, in any case, it is not part of the normal clinical practice in the treatment of the target subjects of the study protocol. In addition, most of Investigators complained the major difficulties to perform the radiological examination at their center and, inevitably, this difficulty has, in many cases, lowered the enrollment rate. Finally, please note that the decision has been shared with the Study Coordinator and is taken having given due consideration to the safety of patients in the study. B) The enrollment period is extended by further 9 months, from 12 to 21 months. Consequently, the total duration of the study, which includes the enrollment period and the successive steps of pre-treatment, treatment and follow-up, will be approximately 25 months. The extension of this period was needed in order to achieve the sample size of 200 patients planned in the protocol, having regard to the recruitment difficulty encountered in most of the centers involved. The term of the enrollment period is now extended to June 30th 2014, therefore it is estimated that the study will be completed by the end of October 2014. C) On this occasion the name and references of the CRO "Opera" will be replaced in the Study Protocol with the name and references of the CRO "Latis", the CRO currently authorized by the Promoter, as already communicated with the "Substantial Amendment Notification No. 3 06.02.2013 - Change in practice management." D) Finally, to communicate the details of the new Dimatex® batch: Batch No. 021810, which expires on September 2014. The new batch certificate was issued on 12.09.2013 by the Laboratorio Farmaceutico CT Srl.