| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
|
| 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 the trial is to demonstrate non-inferiority of treatment with TMC278 when administered as 25 mg q.d. compared to the control group (EFV) in regard to the proportion of virologic responders (plasma viral load < 50 HIV-1 RNA copies/mL, according to TLOVR algorithm) at 48 weeks in ARV-naïve HIV-infected subjects, with a maximum allowable difference of 12%. |
|
| E.2.2 | Secondary objectives of the trial |
Demonstrate:
-non-inferiority of TMC278 compared to control with maximum allowable difference of 10% at 48weeks for primary efficacy endpoint
Evaluate:
-superiority in efficacy of TMC278 compared to control,in case non-inferiority is established
-and compare safety+tolerability of TMC278 when administered as 25mg q.d. vs control over 48and 96weeks
-and compare antiviral activity of TMC278 when administered as 25mg q.d. vs control over 48and96weeks
-and compare immunologic changes in TMC278 group vs those in control group over 48and96weeks
-population pharmacokinetics and the pharmacokinetic/-dynamic Relationships for efficacy+safety of TMC278. Influence of covariates on the population pharmacokinetics will be investigated
Assess:
-evolution of the viral genotype+phenotype over 48and96weeks
-preference-based health states+medical resource utilization for use in future economic evaluations
-treatment adherence,measured by Modified Medication Adherence Self-Report Inventory |
|
| 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 |
A substudy of TMC278-TiDP6-C209 to evaluate the effects of longterm TMC278 25 mg q.d. and efavirenz therapy on body fat and bone mineral density.
The primary objective of the substudy is to demonstrate superiority of treatment with TMC278 when administered as 25 mg q.d. compared to the control group (EFV) in terms of proportion of subjects with ≥ 10% decrease in limb fat from baseline as per dual energy X-ray absorptiometry (DEXA) scan at Week 96.
The secondary objectives are:
- to compare the proportion of subjects with ≥ 10% decrease in limb fat between TMC278 and EFV at Week 48;
- to compare the proportion of subjects with ≥ 20% or ≥ 30% decrease in limb fat between TMC278 and EFV at Week 48 and Week 96;
- to compare the absolute and percent changes from baseline in limb fat, trunk fat, total body fat, and BMD between TMC278 and EFV at Week 48 and Week 96.
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| E.3 | Principal inclusion criteria |
1. Male or female subjects, aged 18 years or older;
2. S (Subject) with documented HIV-1 infection;
3. S has signed the ICF voluntarily;
4. S can comply with the protocol requirements;
5. S has never been treated with a therapeutic HIV vaccine or an ARV drug prior to screening;
6. HIV-1 plasma viral load at screening is ≥ 5,000 HIV-1 RNA copies/mL (assayed by RNA PCR standard specimen procedure);
Note: Retesting of HIV-1 plasma viral load to reassess eligibility will be allowed only once using an unscheduled visit during the screening period.
7. In the judgment of the investigator, it is appropriate to initiate ARV therapy based on the S’s medical condition and taking into account guidelines for the treatment of HIV-1 infection;
Note: Most current treatment guidelines recommend considering initiation of ART when CD4+ cell counts are below 350 cells/µL. However, clinical situations may warrant initiating ART with CD4+ cell counts above 350 cells/µL. Examples of such situations would include rapidly declining CD4+ cell counts over time, high plasma viral load, history of AIDS-defining illnesses, or severe symptoms of HIV infection.
8. Demonstrated sensitivity to TDF and FTC based on results at screening or based on available historical data, when using the lower clinical cut-off (indicated as “Maximal Response”) or the biological cut-off (indicated as “susceptible”) on the screening virco®TYPE HIV-1 result;
9. S agrees not to start ART before the baseline visit;
10. S’s general medical condition, in the investigator’s opinion, does not interfere with the assessments and the completion of the trial.
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|
| E.4 | Principal exclusion criteria |
1. Any previous treatment with a therapeutic HIV vaccine or use of ARVs, incl. use of NVP for the prevention of vertical HIV transmission
2. Having documented genotypic evidence of NNRTI resistance at screening or from historical data avail. in the source docs, i.e. at least 1 of the NNRTI RAMs from follow. list:
A098G
L100I
K101E
K101P
K101Q
K103H
K103N
K103S
K103T
V106A
V106M
V108I
E138A
E138G
E138K
E138Q
E138R
V179D
V179E
Y181C
Y181I
Y181V
Y188C
Y188H
Y188L
G190A
G190C
G190E
G190Q
G190S
G190T
P225H
F227C
M230I
M230L
P236L
K238N
K238T
Y318F
3. Previously documented HIV-2 infection
4. Use of disallowed concomitant therapy from 4 weeks prior to baseline visit
5. Any condition which, in the opinion of the inv., could compromise the S’s safety or adherence to CTP
6. Life expectancy < 6 months
7. S has any currently active AIDS defining illness with follow. exceptions:
- Stable, cutaneous Kaposi Sarcoma (i.e. no pulmonary or gastrointestinal involvement other than oral lesions) that is unlikely to require any form of systemic therapy during trial period
- Wasting syndrome due to HIV infection if, in the inv.’s opinion, it is not actively progressive and its treatment does not require hospitalization or compromise the subject’s safety or compliance to adhere to CTP procedures. If the S is on maintenance therapy for previously diagnosed wasting syndrome, (s)he may be eligible for the trial only if such treatment is not incl. in list of disallowed medications
- Pneumocystis Carinii Pneumonia infection that is considered cured and the acute phase ended at least 30 days ago, and for which currently no therapeutic treatment is required (PCP prophylaxis is allowed, as long as it is not incl. in list of disallowed medications)
- Past occurrence of cryptococcosis that is considered to be fully cured and the acute phase ended at least 30 days ago and/or for which no therapeutic treatment is required
8. Any active clinically significant disease (eg. pancreatitis, cardiac dysfunction, active and significant psychiatric disorder, clinical suspicion of adrenal insufficiency, hepatic
impairment), or findings during screening or medical history or physical examination that in the inv.’s opinion, would compromise the outcome of the trial
9. S has active tuberculosis and/or is being treated for tuberculosis at screening
10. S has known or suspected acute (primary) HIV-1 infection
11. S has one or more of follow. risk factors for QTc prolongation:
- A confirmed prolongation of QT/QTc interval, eg. repeated demonstration of QTcF
(Fridericia correction) interval > 450 ms in the screening ECG
- Pathological Q-waves
- Evidence of ventricular pre-excitation
- Electrocardiographic evidence of complete or incomplete left bundle branch block or
right bundle branch block
- Evidence of 2nd or 3rd degree heart block
- Intraventricular conduction delay with QRS duration > 120 ms
- Bradycardia as defined by sinus rate < 50 bpm
- Personal or family history of long QT syndrome
- Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia
- Syncopal episodes
- Risk factors for Torsade de Pointes (eg. heart failure, hypokalemia, hypomagnesemia)
12. Receipt of any investigational drug or investigational vaccine within 90 days prior to first trial drug administration
13. S enrolled in other clinical trials that incl. any blood sampling with a volume
higher than 50 mL taken over the course of 6 months, specimen
collection, or other interventional procedure. Concurrent participation in non-interventional observational trials is allowed as long as there is no impact on objectives of this trial. Data collected in this trial can be reported in the observ. trial
14. Previously demonstrated clinically significant allergy or hypersensitivity to any of the components of the investigational medication (TMC278) or to components of EFV or TDF/FTC
15. Pregnant or breastfeeding female
16. Female of childbearing potential without use of effective birth control methods or not willing to continue practising these birth control methods from screening onwards until at least 30 days after last intake of study medic.
17. Non-vasectomized heterosexually active males without use of effective birth control methods or not willing to continue practising these birth control methods from screening onwards until 30 days after last intake of study medic.
18. Any grade 3 or 4 laboratory toxicity according to the Division of AIDS (DAIDS) grading table, except:
- grade 3 absolute neutrophil count
- grade 3 platelets
- grade 3 glucose elevation in diabetics
- asymptomatic grade 3 pancreatic amylase elevation
- asymptomatic grade 3 triglyceride / cholesterol (including LDL cholesterol) / glucose elevation
- asymptomatic grade 4 triglyceride elevation
19. Renal impairment: calculated creatinine clearance (CLCr) < 50 mL/min
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| E.5 End points |
| E.5.1 | Primary end point(s) |
proportion of subjects with confirmed and sustained plasma viral load <50 HIV-1 RNA
copies/mL (TLOVR algorithm) at Week 48.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, durability of antiviral activity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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