E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020160 |
E.1.2 | Term | HIV disease |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of 400 mg QD nevirapine extended release (NVP XR) formulation versus 200 mg BID nevirapine immediate release (NVP IR) in ARV therapy naïve HIV-1 infected patients after 48 weeks of treatment.
The objective of the additional extension phase is to collect additional data on the long term efficacy and safety of NVP XR. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate safety and pharmacokinetics of NVP XR and NVP IR. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Pharmacokinetic Substudy: Designated trial centers will participate in the pharmacokinetic substudy that includes intensive blood collection on Day 28. It is planned to include approximately 30 patients within this substudy. A patient who qualifies for the trial will automatically qualify for the PK substudy. A separate informed consent form will be required for participation in the substudy. Only study centers with previous experience and equipped in handling PK samples are eligible for participation in the substudy. It is anticipated that enrollment for the PK substudy will be finished before completion of the main study. In this case, the sponsor will inform the designated centers to continue enrollment for the main study without further enrollment into the PK substudy. |
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E.3 | Principal inclusion criteria |
1. Signed informed consent in accordance with GCP and local regulatory requirements prior to trial participation
2. HIV-1 infected males or females ≥18 years of age with positive serology (ELISA) confirmed by Western blot
3. No previous antiretroviral treatment
4. Males with CD4+ counts >50 - <400 cells/µl or females with CD4+ counts >50 <250 cells/µl
5. Adequate renal function defined as a calculated creatinine clearance (CLCr) greater than or equal to 50 mL/min according to the Cockcroft-Gault formula as follows:
Male: (140 – age in years) x (weight in kg) divided by 72 x (serum creatinine in mg/dl) = CLCr (mL/min).
Female: (140 – age in years) x (weight in kg) divided by 72 x (serum creatinine in mg/dl) x 0.85 = CLCr (mL/min).
6. Karnofsky score >70 (see Appendix 10.4)
7. An HIV-1 viral load of ≥1,000 copies/mL
8. Willingness to initiate CD4+ cell count-guided chemoprophylaxis to prevent important opportunistic infections as defined in Appendix 10.2
9. Willingness to abstain from ingesting substances which may alter plasma study drug levels by interaction with the cytochrome P450 system (listed in Appendix 10.3) during the study.
10. For centers participating in the PK substudy only: Written informed consent in accordance with GCP and local legislation for participation in the PK substudy.
Patients who have successfully completed their week 144 visit of the main trial and given their written informed consent will enter the additional extension phase. |
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E.4 | Principal exclusion criteria |
1. Active drug abuse or chronic alcoholism at the investigator’s discretion
2. Active hepatitis B or C disease, defined as HBsAg-positive and/or HBV-DNA-positive or HCV-RNA-positive. Patients who are HBV DNA positive, HBsAg negative and hepatitis surface antibody positive will be allowed into the trial.
3. Female patients of child-bearing potential who:
a. have a positive serum pregnancy test at screening,
b. are breast feeding,
c. are planning to become pregnant,
d. are not willing to use a barrier method of contraception, or
e. are not willing to use methods of contraception other than ethinyl estradiol containing oral contraceptives.
Note: During participation in this study, females and males have to use barrier methods of contraception in addition or instead of ethinyl estradiol containing oral contraceptives. These barrier methods are: diaphragm with spermicide substance, condom for females, cervical caps and condoms.
4. Laboratory parameters >DAIDS Grade 2
However patients with DAIDs Grade 3 for the following laboratory parameters will be
allowed into the trial: Eosinophils, Total cholesterol, LDL, HDL, Triglycerides, Total protein, Amylase accompanied by a normal lipase.
5. ALT/AST > DAIDS Grade 1
6. Hypersensitivity to any ingredients of the test products
7. Previous use of Viramune® (nevirapine) or any other antiretroviral agents (does not include use of single dose NVP administered with or without an NRTI for the prevention of mother to child transmission at least 6 months prior to enrolment).
8. Resistance to NNRTIs or either one of the components of Truvada® (emtricitabine or tenofovir disoproxil fumarate) or lamivudine (3TC) based on HIV-1 genotypic resistance testing report obtained at screening
9. Patients who are receiving other concomitant treatments which are not permitted, as described in the prescribing information
10. Use of investigational medications (any experimental agent other than the study regimen) within 30 days before study entry or during the trial
11. Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g., interferon, cyclosporin, hydroxyurea, interleukin 2)
12. Patients who have been diagnosed with malignant disease and who are receiving systemic chemotherapy or are anticipated to receive any therapy during their participation in this trial.
13. Patients who in the opinion of the investigator are not candidates for inclusion in the study
14. Patient with Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any lymphoma
15. Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 8 weeks at screening visit
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is sustained virologic response through Week 48.
A virologic response is defined by two consecutive measurements of VL <50 copies/mL, at least two weeks apart. A sustained virologic response has no virologic rebound or change of ARV therapy* through Week 48. The time window of Week 48 is defined as 48 ± 4 weeks from Day 1 (the day a patient starts treatment).
A virologic rebound is defined by two consecutive measurements of VL ≥ 50 copies/mL, at least two weeks apart, after a virologic response.
If there is unconfirmed change of VL status (rebound or response) at Week 48, then
another measurement two weeks later is necessary to confirm whether the virologic rebound or response has occurred. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 48 weeks of treatment |
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E.5.2 | Secondary end point(s) |
1. Time-to-loss-of-virologic response
2. Virologic response by Week 48 as defined by VL <400 copies/mL
3. Time to virologic response
4. Time to new AIDS or AIDS-related progression event or death.
5. Change from baseline in VL and CD4+ cell count at each visit.
6. Genotypic resistance associated with virologic failure. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from week 48 to week 144
2. after 48 weeks
3. between the start of lead-in period and the first viral load <50 copies/ mL prior to the time
when the last enrolled patient is on treatment for 48 weeks
4. throughout the study duration (from start to 144 weeks)
5. at each visit throughout the study
6. throughout the study, whenever virologic failure occurs |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The additonal extension phase will be open label |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Botswana |
Canada |
France |
Germany |
Ireland |
Italy |
Mexico |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
South Africa |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial 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
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An end of trial (EOT) visit will be performed when a patient either completes the entire trial at Week 144 or discontinues early (note: Week 144 is the maximum treatment duration allowed for each patient). This visit should occur within one week of the last dose of study drug to evaluate efficacy, AEs/SAEs and the final laboratory test results. The EOT visit for early discontinuation is conducted to collect efficacy and safety information from patients who discontinue from Trial 1100.1486.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |