New Era Study: Treatment With Multi Drug Class (MDC) HAART in HIV Infected Patients

NEW ERA STUDY - HIV and Eradication: A Multicenter, Open-label, Non-randomized Trial to Evaluate Treatment With Multi-drug Class (MDC) HAART and Its Impact on the Decay Rate of Latently Infected CD4+ T Cells Incl. Amendment 1.0

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.

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.

1. Inclusion Criteria:

   For all patients:

   • HIV-infected patient
   • Age greater 18 years
   • No acute AIDS-defining disease or history of AIDS- defining disease
   • CD4-cell nadir above or equal 200 cells/µL
   • Hemoglobin greater 8 g/dl
   • Neutrophil count greater 750 cells/µL
   • Platelet count greater 50.000 cells/µL
   • AST/ALT below 5x upper limit of normal range
   • No evidence for drug intolerability
   • No prior use of an HIV integrase inhibitor or CCR5 antagonist
   • No presence of malignancy (requiring active treatment and malignancy within 5 years prior to enrolment (even if in complete remission)
   • No significant underlying disease (non-HIV) that might impinge upon disease progression or death
   • No history of alcohol or other substance abuse or other condition which in the opinion of the investigator would interfere with the patient compliance or safety.
   • Written informed consent
   • For males and premenopausal females use of acceptable methods of birth control during the entire study and for 6 weeks thereafter
   • No pregnancy (for premenopausal women: negative serum or urine pregnancy test within 48 hours prior to initiating study medications)
   • No breastfeeding

   For chronically HIV-infected patients (CHI):

   • Continuous plasma viral load below 50 copies/ml for the preceding 36 months under HAART (two or less single viral load blips up to 500 copies/ml are allowed)
   • Stable HAART (for at least 3 months) prior to the Screening visit consisting of 2 NRTI + 1 PI
   • No history of virological failure
   • No documented resistance to PI and NRTI
   • CCR5-tropic virus

   For patients with primary HIV infection (PHI):

   • Detectable plasma viral load
   • ELISA positive or negative and Western Blot negative or positive with less or equal 2 bands at screening visit
   • No primary resistance to PI´s and NRTI´s
   • CCR5-tropic virus

2. Exclusion criteria:

Evidence for drug intolerability or contraindication concerning any drug foreseen for MDC HAART

• Documented HIV-1 resistance to PI and/or NRTI.

• CD4 nadir <200/µL

• Acute AIDS-defining disease or history of AIDS-defining disease

• CHI: preceding virological failure

• History of alcohol or other substance abuse or other condition which in the opinion of the investigator would interfere with the patient compliance or safety.

• Any of the following abnormal laboratory test results in screening:

  1. Hemoglobin < 8 g/dL
  2. Neutrophil count < 750 cells/µL
  3. Platelet count < 50,000 cells/µL
  4. AST or ALT > 5x the upper limit of normal

• Presence of malignancy (requiring active treatment and malignancy within 5 years prior to enrolment (even if in complete remission)

• Significant underlying disease (non-HIV) that might impinge upon disease progression or death

• Prior use of any experimental HIV- Integrase-Inhibitor or CCR5-antagonist.

• Patient is pregnant or breastfeeding, or expecting to conceive (within the duration of the study). Patient is expecting to donate eggs (within the duration of the study). Patient is expecting to donate sperm (within the duration of the study).

• Contraindications for Maraviroc (Celsentri®) or Raltegravir (Isentress®) according to the respective summary of product characteristics (see also product informations attached to the protocol) (Hypersensitivity to the active substances or any of the excipients).