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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020161 |
E.1.2 | Term | HIV infection |
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 purpose of this study is to compare the efficacy of fostemsavir
relative to placebo, when given on the background of a failing regimen,
by determining the mean change in log10 HIV-1 RNA from Day 1 at Day
8 in the Randomized Cohort |
|
E.2.2 | Secondary objectives of the trial |
-assess the efficacy of fostemsavir 600 mg BID relative to placebo, when given on the background of a failing regimen
-assess the durability of the subjects’ responses to fostemsavir when given with an OBT by determining the proportion of subjects with plasma HIV-1 RNA < 40 c/mL at Week 24, Week 48, and Week 96
-assess the safety and tolerability of fostemsavir + OBT in subjects by measuring frequency of serious adverse events, adverse events
-assess disease progression during OBT as measured by the occurrence of new AIDS-defining events or death in the Randomized Cohort.
-assess the emergence of antiretroviral drug resistance among subjects with protocol defined virologic failure (VF) in the Randomized Cohort.
-assess the efficacy of fostemsavir + OBT, by examining the changes from baseline in log10 HIV-1 RNA, CD4 + T-cell counts, and the percentage of CD4 + T cells through Week 24, Week 48, and Week 96 in the Randomized Cohort. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed and written informed consent
2) Target population:
-) Men and non-pregnant women with chronic HIV-1 infection
-) Age 18 and older
-) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment/screen failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented. and all screening requirements repeated. Re-enrollment is at the discretion of the medical monitor in discussion with PI.
-) Antiretroviral-experienced with documented historical or baseline
resistance, intolerability, and/or contraindications to antiretrovirals in at
least three classes
-) Failing current antiretroviral regimen with a confirmed plasma HIV-1
RNA of more or equal to 400 c/mL (first value from Investigator within 6
months of screening visit, with the second value obtained from
Screening labs). Subjects with a screening HIV-1 RNA <400 c/mL should
be counted as screen failures; repeat testing is not permissible.
-) Must have at least one fully-active and available agent in < or = 2 ARV classes, based on current and/or documented historical resistance
testing, taking into account tolerability and other safety concerns
3) Age and Reproductive Status
-) Willingness to use approved highly effective methods of contraception
to avoid pregnancy (men and women of child bearing potential only).
-) Males and Females, ages 18 years of age or older (or minimum age as
determined by local regulatory or as legal requirements dictate)
-) Women of childbearing potential (WOCBP) must have a negative
serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 24 hours prior to the start of study drug.
-) Women must not be breastfeeding
-) WOCBP must agree to follow instructions for method(s) of
contraception for the duration of treatment with the Attachment
Inhibitor and for at least 60 hours after drug exposure.
-) Males, whether azoospermic or not, who are sexually active with
WOCBP must use condoms and agree to follow instructions for
method(s) of contraception for the duration of treatment with the
Attachment Inhibitor and for at least 60 hours after drug exposure.
-) WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However, they must still undergo
pregnancy testing as described in protocol. |
|
E.4 | Principal exclusion criteria |
1) Any other clinical condition (including but not limited to substance
use) or prior therapy that, in the opinion of the Investigator, would
make the subject unsuitable for the study
2) Physical and Laboratory Test Findings
-) Chronic untreated HBV (however, patients with chronic treated HBV
are eligible)
-) HIV-2 infection
-) ALT or AST > 7 x ULN
-) Alkaline Phosphatase > 5 x ULN
-) Bilirubin of more or = 1.5 x ULN (unless subject has Gilbert's disease,
and/or is currently on atazanavir, and has predominantly unconjugated
hyperbilirubinemia)
-) History of decompensated cirrhosis or active decompensated cirrhosis
-) History of congestive heart failure or congenital prolonged QT
syndrome
-) Hemoglobin < 8.0 g/dL (Randomized Cohort); Hemoglobin < 6.0 g/dL
(Non-Randomized Cohort)
-) Platelets < 50,000 cells/mm3 (Randomized Cohort); Platelets <
20,000 cells/mm3 (Non-Randomized Cohort);
-) Confirmed QT value > 500 msec at Screening or Day 1
-) Confirmed QTcF value > 470 msec for women and > 450 msec for men
at Screening or Day 1
-) Confirmed PR Interval > 260 msec (severe first degree AV block) at
Screening or Day 1
-) Confirmed second or third degree heart block at Screening or Day 1
-) Current or anticipated treatment with any of the following
medications: rifampin, Hypericum perforatum (St. John's wort),
efavirenz, nevirapine, carbemazepine, phenobarbital, phenytoin, amiodarone disopyramide, dofetilide, ibutilide,
procainamide, sotalol, and quinidine. Simvastatin and lovastatin should
not be co-administered with boosted protease inhibitors.
-) Participation in an experimental drug and/or HIV-1 vaccine trial(s)
within the previous 30 days (Randomized Cohort only)
3) Other Exclusion Criteria
-) Prisoners or subjects who are involuntarily incarcerated
-) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The efficacy of fostemsavir, relative to placebo, is assessed using the
mean change in log10 HIV-1 RNA from Day 1 at Day 8 as determined by
ANCOVA in the randomized cohort. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
-The proportions of subjects in the randomized cohort with HIV-1 RNA decreases from Day 1 that exceed 0.5 log10 c/mL and 1 log10 c/mL are determined by comparing each subject’s HIV-1 RNA Day 1 measurement to their Day 8 measurement. This is an mITT analysis based on treated subjects that classifies subjects without HIV-1 RNA at Day 1 or Day 8 as failures.
-The durability of response (HIV-1 RNA < 40 c/mL) at Week 24, Week 48, and Week 96 of OBT is assessed using the FDA snapshot algorithm. This is an mITT analysis based on treated subjects that classifies subjects without HIV-1 RNA at Week 24 or those who changed OBT due to lack of efficacy through Week 24 as failures.
-The frequency of SAEs, AEs leading to discontinuation, and Grade 3-4 laboratory abnormalities during OBT are tabulated from Case Report Forms (CRFs) and laboratory data.
-Disease progression during OBT is assessed using the occurrence of new AIDS-defining events (CDC Class C events) or death as tabulated from CRFs.
-Drug resistance is assessed through phenotypic and genotypic resistance testing of isolates from subjects identified as meeting the criteria for virologic failure.
-The changes in CD4+ T-cells counts and percentages, for fostemsavir and placebo when given with failing background therapies, are determined using the mean changes from Day 1 at Day 8 in the randomized cohort.
-The changes from baseline in HIV-1 RNA, CD4+ cell counts, and percentage of CD4+ T-cells, for fostemsavir when given with OBT, are assessed using laboratory results collected through Week 24, Week 48, and Week 96 in the randomized cohort.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
week 24, week 48, week 96 |
|
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Denmark |
France |
Germany |
Greece |
Ireland |
Italy |
Mexico |
Netherlands |
Norway |
Peru |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
South Africa |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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Last follow-up visit of the last subject |
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 23 |