Ignite Creation Date:
2024-05-05 @ 9:32 PM
Last Modification Date:
2024-10-26 @ 10:06 AM
Study NCT ID:
NCT00908544
Status:
COMPLETED
Last Update Posted:
2019-08-28
First Post:
2009-05-26
Brief Title:
New Era Study Treatment With Multi Drug Class MDC HAART in HIV Infected Patients
Sponsor:
MUC Research GmbH
Organization:
MUC Research GmbH
Study Overview
Official Title:
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 10
Status:
COMPLETED
Status Verified Date:
2019-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NewEra
Brief 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 N40 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 NRTIs 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
All patients will be started on a multi-drug HAART including two Nucleoside-Reverse-Transcriptase-Inhibitors NRTIs 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 MVCRAL 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 bid 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 bid 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 bid without regard to food if the co-administered PI is Fosamprenavir or Tipranavir
In both treatment groups NRTIs or PIs can be replaced by other NRTIs or PIs 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 heshe 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 ScreeningBaseline 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_v33 Protocol EudraCT 2008-002070-35 date 6112014 approved BfArM on 04022015 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 SAEs
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 subjectpatient 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 individuals listed on the sponsor
For all serious adverse experiences the Serious Adverse ExperiencePregnancyOverdose 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 riskbenefit warrants the patients continuation in the study
Suspected Unexpected Serious Adverse Reactions SUSARs
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 05-15 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 3533-37 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 005 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 005
The null hypotheses will be accepted if the p-value of the test greater than 005
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
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 MVCRAL 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 bid 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 bid 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 bid without regard to food if the co-administered PI is Fosamprenavir or Tipranavir
In both treatment groups NRTIs or PIs can be replaced by other NRTIs or PIs 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 heshe 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 ScreeningBaseline 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_v33 Protocol EudraCT 2008-002070-35 date 6112014 approved BfArM on 04022015 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 SAEs
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 subjectpatient 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 individuals listed on the sponsor
For all serious adverse experiences the Serious Adverse ExperiencePregnancyOverdose 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 riskbenefit warrants the patients continuation in the study
Suspected Unexpected Serious Adverse Reactions SUSARs
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 05-15 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 3533-37 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 005 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 005
The null hypotheses will be accepted if the p-value of the test greater than 005
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| IISP 35576 | OTHER_GRANT | MSD | None |
| 2008-002070-35 | EUDRACT_NUMBER | None | None |
| 4034932 | OTHER | None | None |
| 08101 | OTHER | None | None |
| ID 8879 | OTHER_GRANT | None | None |