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TMC-114 Expanded Access Program
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Combination studies of TMC-114 (PI) + TMC-125 (NNRTI)
For patients looking for other options for access to TMC-114, the company Tibotec is conducting two studies for highly treatment experienced patients combining both TMC-114, a protease inhibitor, with TMC-125, a NNRTI for NNRTI drug resistance. In preliminary studies TMC-125 demonstrates antiviral activity against NNRTI drug resistance.
Although the CD4 cutoff for entry into the TMC-114 Expanded Access Program is 200, exceptions can be made. As well, consideration will be afforded to adding other non-approved HIV drugs depending on whether there is a pk interaction between TMC-114 & the drug.
FOR INFORMATION CALL:
1-866-889-2074 (within US) or
e-mail: TMC114-C226@i3research.com or
http://www.tibotec.com
Summary of access program study:
This is a study to provide early access to TMC114 for HIV-1
infected subjects, who have failed multiple antiretroviral (ARV)
regimens and who are ineligible for participation in any other
Tibotec-sponsored HIV trial.
In addition, information on safety and tolerability of TMC114 in combination with low-dose ritonavir (RTV) and other ARVs in highly ARV-experienced HIV-1 infected subjects with limited to no treatment options will be assessed.
Once treatment has been initiated, subjects will be instructed to
follow the visit schedule based on routine clinical care.
Recommended visits should be planned 4 and 12 weeks following
initiation of TMC114 in combination with low-dose RTV and other
ARVs and every 12 weeks thereafter while on therapy. Treatment
with trial medication will be continued until treatment-limiting
toxicity, loss to follow-up, withdrawal, pregnancy, discontinuation
of TMC114 development or when TMC114 becomes commercially
available to the subject.
The primary objective is to provide early access to TMC114 for highly ARV-experienced HIV-1 infected subjects who have failed multiple ARV regimens.
4.2 Secondary Objectives
The secondary objective is to gather information on the safety and tolerability of TMC114 in combination with low-dose RTV and other ARVs.
5.2.2 INCLUSION CRITERIA
Subjects who meet all of the following criteria are eligible for this trial.
1. Subject has voluntarily signed the informed consent before initiation of study procedures.
2. Subject with documented HIV-1 infection.
3. Male or female subject over 18 years of age.
4. Subject has limited or no treatment options due to virological failure or intolerance to multiple ARV regimens.
5. Subject is at least 3 class experienced and has previously received 2 different PI based regimens.
6. CD4 cell count >200 cells/mm3.* (exceptions can be made if CD4s are >200.
7. Subject is not achieving adequate virologic suppression on his/her current regimen and at risk of clinical or immunologic progression.
5.2.3 EXCLUSION CRITERIA
Subjects meeting one or more of the following criteria cannot be selected.
1. Primary HIV-1 infection.
Note: Subjects with primary HIV-1 infection will only be allowed in the trial if they have documented resistance to all currently approved PIs. For these subjects, inclusion criteria 4, 5, 6 and 7 may not apply.
2. Subject is eligible for other Tibotec sponsored HIV trials.
Note: Subjects eligible for any other Tibotec sponsored HIV trial but located more than 60 miles away from a site participating in such trial, will be considered eligible for trial TMC114-C226.
3. Prior or current participation in a trial with TMC114.*
4. Any condition (including but not limited to alcohol and drug use), which, in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol.
5. Use of disallowed concomitant therapy. (See Section 5.3.8)
6. Use of investigational medication within the last 30 days (consideration may be given to use of investigational agents). The following exceptions apply:
- abacavir/lamivudine and tenofovir/emtricitabine fixed dose combinations (if applicable, according to local approval);
- tipranavir.
7. Any active clinically significant disease (e.g., cardiac dysfunction, pancreatitis, acute viral infection) or findings during screening of medical history or physical examination that is not either resolved or stabilized for at least 30 days before the screening phase of the trial.
8. Pregnant or breast-feeding female.
9. Female subject of childbearing potential not using effective non-hormonal birth control methods or not willing to continue practicing these birth control methods from screening until the last trial related activity.
Note: Hormonal based contraception may not be reliable when taking TMC114, therefore to be eligible for this study, women of childbearing potential who may have vaginal intercourse should either:
(1) use a double barrier method to prevent pregnancy (i.e., using a condom with spermicide, with either diaphragm or cervical cap)
or
* May not apply for HIV-infected subjects with previous participation in trial TMC114-C209 or in sponsor selected TMC114 trials.
(2) use hormonal based contraceptives in combination with a barrier contraceptive (i.e., male condom with spermicide, diaphragm or cervical cap or female condom)
or
(3) use an intra uterine device (IUD) in combination with a barrier contraceptive (i.e., male condom with spermicide, diaphragm or cervical cap or female condom)
or
(4) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile).
Note: Women who are postmenopausal for at least 2 years, women with total hysterectomy and women with tubular ligation are considered of non-childbearing potential.
10. Subjects with the following laboratory abnormalities as defined by a standardized grading scheme based on the DAIDS table (updated version from December 2004, see Section 7.2):
- Any grade 3 or 4 toxicity of the selected laboratory parameters as described in the section Safety (see Section 5.4.4) with the following exceptions:
- Subjects with pre-existing diabetes or asymptomatic glucose elevations of grade 3 or 4.
- Subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.
11. Subject with clinical or laboratory evidence of active liver disease, liver impairment/dysfunction or cirrhosis irrespective of liver enzyme levels.
Note: Subjects co-infected with chronic hepatitis B or C will be allowed to enter the trial if their condition is judged to be clinically stable. Subjects diagnosed with acute viral hepatitis at screening will not be allowed to enroll.
12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication (TMC114) or RTV.
Note: TMC114 is a sulfonamide. Subjects who previously experienced a sulfonamide allergy will be allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the sulfonamide class and TMC114 has been identified in subjects participating in Phase II trials.
5.2.4 PROHIBITIONS AND RESTRICTIONS
All HIV-infected subjects should be advised to take the necessary precautions to reduce the risk of transmitting HIV.
Since the effects of TMC114 on conception are unknown, non-vasectomized male subjects and/or female subjects of childbearing potential having heterosexual intercourse are advised to use one of the following birth control methods:
- a condom with spermicide combined with either hormonal contraceptives, IUD, diaphragm, cervical cap or female condom; or
- practice abstinence.
These precautions apply from screening onwards until 4 weeks after the last study drug administration or until the Week 4 post trial treatment follow-up contact in case of premature discontinuation.
The use of above mentioned birth control methods does not apply if the male HIV-infected subject has been vasectomized at least one month prior to screening or if the female sexual partner has had a tubal ligation or a total hysterectomy or if she is postmenopausal for at least 2 years.
For details on the existing data in regard to the reproductive toxicity of TMC114, please see the current Investigator's Brochure.
Women should not breast-feed when taking TMC114, as the effects to their newborn child are unknown. They should not breast-feed if they are HIV infected and should talk to their physician about the best way to feed their child. They should be aware that there is a chance that HIV could be transmitted through breast-feeding.
5.2.5 REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
Subjects may be withdrawn from the trial if:
1. a serious adverse event (SAE) occurs;
2. the subject starts treatment with one of the medications reported on the list of disallowed medications (see Section 5.3.8). The sponsor should then be contacted for decision;
3. the subject fails to comply with the protocol or study staff requirements;
Subjects must be withdrawn from the trial if:
1. they withdraw their consent;
2. they are lost to follow-up;
3. the investigator considers it is in the best interest of the subject, for safety reasons, that he or she be withdrawn;
4. pregnancy has been confirmed;
5. the subject experiences a grade 3 or 4 cutaneous reaction/rash (according to the DAIDS scale; see Section 7.2);
6. the subject experiences a confirmed lipase elevation of grade 3 or 4, which persists after 14 days following the interruption of all study medications, or if the toxicity recurs more than twice;
7. the subject experiences, after study medication interruption because of a confirmed grade 3 increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), a confirmed recurrence of grade 3 or 4 increase in ALT or AST. For subjects with hepatitis B or C infection present at screening, please see Section 5.5.3 for toxicity management plans;
8. the subject experiences a grade 4 AE or confirmed grade 4 laboratory abnormality. Exceptions are, unless clinical assessment foresees an immediate health risk to the subject:
- subjects with pre-existing diabetes or with non-fasted asymptomatic glucose grade 4 elevations;
- subjects with non-fasted asymptomatic triglyceride elevations of grade 4;
- subjects with a grade 4 AE considered not related or doubtfully related to the study medication;
9. the subject is newly diagnosed with acute viral hepatitis while participating in the trial;
10. discontinuation of TMC114 development;
11. TMC114 is made commercially available to them.
The date and the reason for discontinuation must be noted on the appropriate page of the electronic Case Report Form (eCRF) or paper CRF. Unless the subject withdraws consent, each subject prematurely discontinuing the trial must be seen for a final evaluation (withdrawal visit) and the Trial Termination page and Investigator's Signature page of the (e)CRF will be completed. A post trial treatment follow-up contact will be performed for all subjects 4 weeks after the last dose of study medication during the study.
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