New Era Study: Treatment With Multi Drug Class (MDC) HAART in HIV Infected Patients
Condition: HIV Infections
MeSH terms: Infections; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Interventional

Summary: 
      This is a multi-center, open-label, non-randomized proof-of-concept trial. Two cooperating
      HIV-specialized centres represented by Dr. med. Hans Jaeger and Prof. Dr. Johannes Bogner are
      planning to perform an IIT (investigator initiated trial) with the goal to eradicate HIV in
      N=40 HIV-infected patients with either primary infection or chronic infection and successful
      HAART (Highly Active Antiretroviral Treatment) of several years.

      All patients will be started on a multi-drug HAART including two
      Nucleoside-Reverse-Transcriptase-Inhibitors (NRTI´s), one Protease-Inhibitor (PI), a
      CCR5-inhibitor and an Integrase-Inhibitor (INI). Decay of viral reservoirs like latently
      HIV-infected CD4+ T-cells will be monitored over time.
    

Detailed description: 
      1. Recruitment and Treatment:

      Recruitment will be stratified according to stage of HIV-infection and pre-treatment:

        -  Stratum I (PHI patients):

      Patients presenting with primary HIV infection

        -  Stratum II (CHR patients):

      Chronically HIV-infected patients with suppressed plasma viral load for ≥36 months under
      continuous HAART (Highly Active Antiretroviral Therapy).

      CHR and PHI patients will be treated with an antiretroviral combination of five approved
      substances (Multi-Drug Class HAART= MDC HAART). Every regimen will contain Maraviroc and
      Raltegravir.

      MDC HAART consisting of:

      2 NRTI + 1PI + 1 CCR5 antagonist (= Maraviroc; MVC) + 1 INI (= Raltegravir; RAL).

      The patients of the PHI-group will be immediately treated with MDC HAART for a duration of
      ≥5-7 years.

      The patients of the CHR-group will be treated with MDC HAART after a 6-month observational
      lead-in phase for measuring laboratory parameters. Then HAART will be intensified with the
      respective missing drug classes of MDC HAART (MVC+RAL). The respective treatment time will be
      2 years up to a Maximum of 7 years from baseline.

      Dosing of antiretrovirals including study drugs Raltegravir and Maraviroc will be according
      to standard dosing as outlined in respective product informations (attached).

        -  Patients will take Raltegravir 400 mg (one 400 mg tablet) PO b.i.d. (without regard to
           food). Raltegravir which can be taken at any time of day but should be taken at the same
           time each day.

        -  Patients will take Maraviroc 150 mg (one 150 mg tablet) PO b.i.d. (without regard to
           food) if the co-administered PI is RTV-boosted Lopinavir, RTV-boosted Atazanavir,
           RTV-boosted Saquinavir, RTV-boosted Darunavir. Patients will take Maraviroc 300 mg (two
           150 mg tablets) PO b.i.d. (without regard to food ) if the co-administered PI is
           Fosamprenavir or Tipranavir

      In both treatment groups NRTI´s or PI´s can be replaced by other NRTI´s or PI´s in case of
      intolerability or other reasons at the discretion of the investigator.

      Other treatments which are initiated by the treating physicians and which may have a
      potential impact on viral reservoirs (like valproic acid) or immunomodulators will not be
      discouraged during the course of the study.

      If new antiretroviral agents will be approved or available through expanded access programs
      during the course of the study that might be beneficial for a study patient at the discretion
      of the treating physician, the treatment regimen can be modified based on current knowledge
      (=addition of new antiretroviral agent or replacement of drugs of the regimen). Patients will
      not be excluded from the study unless they reach the virological endpoint.

      2. Study Procedures:

      Each potential patient has to be informed about the study contents by the investigator and to
      sign the informed consent if he/she wants to participate to the study.

      Then Each patient will be assigned to a unique allocation number at the first screening
      visit. A single patient cannot be assigned to more than one allocation number. Allocation
      number will be provided by the coordinating study centre.

      Patients who meet the eligibility requirements will start their medication at baseline.

      Monitoring of patient safety will be performed at all study visits; Specific laboratory
      measures are performed at a single visit after month 6 in all patients.

      Visit time schedule:

      - PHI-group: Screening/Baseline, Month 1, Month 3, Month 6 and following half-yearly

      - CHI-group: Month -6 (Screening), Month -3 (Pre-baseline), Baseline, Month 1, Month 6 and
      following half-yearly Post Tx visits after pre-mature and regular discontinuation (including
      HAART interruption due to eradication, as defined . Follow-up visits post Tx (PFU1, PFU2,
      PFU3) are foreseen at months 3, 6 and 12.

      According to the New Era study protocol, treatment can be interrupted in case of reaching
      undetectability of HIV-1 RNA in plasma and proviral DNA in PMBC. Because there are needed
      more virologic, immunologic or genetic markers to better predict virus control after
      treatment interruption, an approved Amendment (MUC_NewEra_v3.3 Protocol: EudraCT:
      2008-002070-35 date: 6.11.2014; approved (BfArM) on 04.02.2015) has foreseen to conduct one
      additional blood sampling with the aim to better characterize and discriminate the New Era
      patients in terms of immunologic, virologic and other laboratory parameters

      3. Safety Management:

      At all visits, safety measurements of clinical chemistry, hematology and virology and
      physical examination will be conducted. All adverse events will be recorded.

      Treatment naïve (PHI) female patients of childbearing potential will have pregnancy test
      performed at Screening, Baseline, Month 1, Month 3, Month 6 and following half-yearly until
      Month 90.

      Pretreated (CHI) female patients of childbearing potential will have pregnancy test performed
      at Screen, 6 Month prior to Baseline, 3 Month prior to Baseline, at Baseline, Month 1, Month
      3, Month 6 and following half-yearly until Month 54.

      Serious Adverse Events (SAE´s):

      Any serious adverse experience, whether or not there is a suspected causal relationship to
      the investigational product (including death due to any cause), which occurs to any
      subject/patient entered into this study or within 14 days following cessation of treatment or
      within the established off therapy follow-up period for safety described in the protocol,
      whether or not related to the investigational product, must be reported within 24 hours to
      one of the individual(s) listed on the sponsor.

      For all serious adverse experiences the Serious Adverse Experience/Pregnancy/Overdose Case
      Report Form (SAE Form) will be completed. In addition, every single SAE will be recorded at
      the respective study visit in the Case Report Form.

      Each SAE will be fully investigated and, if drug related, a decision will be made as to
      whether the risk/benefit warrants the patient´s continuation in the study.

      Suspected Unexpected Serious Adverse Reaction´s (SUSAR's):

      The Sponsor will report all SUSARs according to the standards for reporting SUSARs which are
      defined in 'Detailed guidance on the collection, verification and presentation of adverse
      reaction reports arising from clinical trials on medicinal products for human use - April
      2006' and in accordance with all applicable global laws and regulations. SUSAR reports will
      include all informations required according to the Council for International Organizations of
      Medical Sciences CIOMS I reporting form.

      The Sponsor who is non-commercial and not Marketing Authorization Holder (MAH) for any of the
      Investigational Medicinal Products (IMPs) will report all relevant information about a
      suspected unexpected serious adverse reaction (SUSAR) which occurs during the course of a
      clinical trial and is fatal or life-threatening as soon as possible to competent authority
      (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM), the relevant Ethics Committees,
      the investigators and the manufacturers of the study drugs. This needs to be done not later
      than 7 days after the Sponsor was first aware of the reaction. Any additional relevant
      information should be sent within 8 days of the report.

      A Sponsor will report unexpected serious adverse reaction (SUSAR) which is not fatal or
      life-threatening as soon as possible, and in any event not later that 15 days after the
      Sponsor is first aware of the reaction.

      The sponsor will inform all investigators concerned of findings that could adversely affect
      the safety of study subjects. If appropriate, the information can be aggregated in a line
      listing of SUSARs in periods and the volume of SUSARs generated. This line listing should be
      accompanied by a concise summary of the evolving safety profile of the investigational
      medicinal product.

      If a significant safety issue is identified, either upon receipt of an individual case report
      or upon review of aggregate data, the sponsor will issue as soon as possible a communication
      to all investigators.

      A safety issue that impacts upon the course of the clinical study or development project,
      including suspension of the study program or safety-related amendments to study protocols
      should also be reported to the investigators.

      Data Safety Monitoring Board (DSMB):

      The study will be monitored by an independent external Data Safety Monitoring Board (DSMB)/
      Data Monitoring Committee (DMB). The DSMB will provide recommendations to the Oversight
      Committee. The Oversight Committee (consisting of the sponsor and coordinating investigator
      Dr. med. Hans Jaeger and principal investigator Prof. Johannes Bogner) will provide the
      overall scientific direction for the trial, and will receive and decide on any
      recommendations made by the DSMB. The Oversight Committee must approve all scientific reports
      concerning the main findings of the trial. The membership, procedures, functions and
      responsibilities of the Oversight Committee and DSMB will be identified in the New Era DSMB
      Charter.

      Annual Safety Report (ASR):

      In addition to the expedited reporting required for SUSAR, Sponsor will submit once a year
      throughout the clinical trial (or on request) a safety report to the competent authority
      (BfArM), and the relevant Ethics Committees of the concerned Member States.

      4. Data Analysis:

      This proof-of-concept study using a small, targeted number of subjects is carried out to
      determine if eradication of HIV is possible. A design with a placebo was discouraged in the
      light of possible eradication. The chronically infected patients serve as their own controls.
      Prior to baseline, these patients are monitored while on persistently suppressive HAART
      lasting already for at least 36 months and then switched to multi-drug class HAART.

      Based on the assumption, that MDC (multi-drug class) HAART with Raltegravir and Maraviroc
      leads to a mean reduction of at least one 1 log in patients with PHI and assuming a standard
      deviation of 1 and a 95% confidence interval (0.5-1.5 log) with a width of 1, the sample size
      is calculated at ≥16 (assumption of normal distribution).

      Intensification of HAART with Raltegravir and Maraviroc in chronically infected HIV-patients
      may have similar effects (Ramratnam B, J Acquir Immune Defic Syndr 2004; 35:33-37). Sample
      size calculation can be used also for chronically infected HIV-patients.

      A sample size of 40 patients (20 primary infected patients (Stratum I, PHI) and 20
      chronically infected patients (Stratum II, CHR) was chosen. Drop-outs in the first 12 months
      will be replaced.

      In the course of this study no gender specific differences are expected. The application of
      Maraviroc and Raltegravir does not differ in male and female patients. The proportion of male
      and female patients will probably be in accordance with the epidemiologic data in Germany.

      Hypothesis:

      The hypotheses of this study is, that with MDC HAART, a mean reduction in proviral DNA of 1
      log can be achieved by 36 months.

      Null hypotheses H0: Mean reduction of proviral DNA < 1 log. Alternative hypotheses H1: Mean
      reduction of proviral DNA ≥1 log Level of significance : 0.05 Statistical test: One-tailed
      paired t-test

      The null hypotheses will be rejected if the p-value of the test is less than the significance
      level (0.05).

      The null hypotheses will be accepted if the p-value of the test greater than 0.05.

      Statistical Methods:

      For accepting or rejecting the primary hypothesis (of the trial, one-tailed paired t-test
      will be used.

      Performed analysis will be descriptive and explorative.
    

Intervention name(s): PHI-patients; CHI-patients
Intervention type(s): Other; Other
Intervention description(s): Treatment initiation with multi drug class (MDC) HAART. 2 NRTI + 1 PI/r + Maraviroc + Raltegravir; Treatment intensification of PI-based HAART with Maraviroc and Raltegravir. 2 NRTI + 1 PI/r + Maraviroc + Raltegravir
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV-infection; Primary HIV-infection; Proviral DNA; Eradication; Multi drug class HAART