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Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: J.R.E. on June 16, 2007, 11:23:01 am
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Boehringer Ingelheim Initiates SPRING Study Of Aptivus(R) (tipranavir) Capsules In Diverse Group Of Highly Treatment-Experienced HIV Patients
Main Category: HIV / AIDS News
Article Date: 15 Jun 2007 - 0:00 PDT
|Clinical Trials / Drug Trials
Boehringer Ingelheim Pharmaceuticals, Inc., makers of Aptivus(R) (tipranavir) capsules, announced today that it has begun to enroll patients in the SPRING study. The goal of the SPRING study, which will be conducted at 72 sites across eight countries, is to enroll 200 women and 200 men who are HIV-positive and highly treatment- experienced. A diverse female and male population including, but not limited to, White, Black, Hispanic, Asian and American Indian patients will be recruited, making SPRING one of the largest racially, ethnically and gender diverse international studies of highly treatment-experienced HIV-1 infected patients. Additionally, SPRING is the largest randomized controlled trial to evaluate the utility of therapeutic drug monitoring (TDM) in highly treatment- experienced HIV patients.
The SPRING (Safety, efficacy and Pharmacokinetics of tipRanavir boosted with low dose ritonavir (500 mg/200 mg) twice daily IN 400 racially and Gender diverse HIV positive treatment-experienced population) study is a Phase IIIb, open-label, multicenter, multinational trial with a primary endpoint of treatment response at 48 weeks, defined as a viral load <50 copies/mL at two consecutive measurements at least five days apart. Two hundred patients will be included in a randomized evaluation to assess the impact of TDM on the efficacy and safety of APTIVUS co-administered with ritonavir (APTIVUS/r). TDM is the measurement of specific drug levels in a patient's blood at certain intervals of time that is used to tailor medication dosages to fit the specific needs of the individual patient. (i)
"Studies have indicated that the efficacy of antiretroviral treatments may vary across races and genders," explained Dr. Kathleen Squires, Director, Division of Infectious Diseases and Environmental Medicine and SPRING Coordinating Investigator, Thomas Jefferson University, Philadelphia. "Therefore, SPRING is designed to provide insight into potential treatment differences for patient populations such as women and ethnic groups."
Worldwide, there are more HIV-positive women than ever before, with nearly 18 million now living with the disease. Racial and ethnic minorities are also being disproportionately affected by HIV. In the United States, half of AIDS diagnoses were among African-Americans and 20 percent were among Hispanics over the three-year period from 2001 to 2004. (ii)
About SPRING
The SPRING study will enroll patients in 72 sites in the United States, Canada, Mexico, Germany, Italy, Spain, Argentina and Brazil. Patients 18 years and older will have received prior treatment from at least three classes of antiretroviral agents and have documented resistance to at least one protease inhibitor. At screening, patients will have a CD4 cell count of greater than or equal to 50 cells/mm3 and a HIV-1 viral load greater than or equal to 1,000 copies/mL.
All 400 patients entered in the trial will begin the study by receiving the standard dose of 500 mg of APTIVUS co-administered with 200 mg of ritonavir twice daily in conjunction with an optimized background regimen. Two hundred patients randomized to the standard APTIVUS/r dosing regimen will continue to receive this regimen for 48 weeks. The other 200 patients who were randomized to the TDM evaluation may have their dose of APTIVUS or ritonavir modified depending in part on drug concentrations measured at various time intervals.
For additional information on inclusion and exclusion criteria and SPRING study sites, visit http://www.clinicaltrials.gov.
The APTIVUS labeling includes boxed warnings for reports of both fatal and non-fatal intracranial hemorrhage (ICH) and reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.
The most commonly reported adverse events in patients taking APTIVUS/r are diarrhea, nausea, fatigue, headache and vomiting. The most common laboratory abnormalities are elevated liver enzymes (AST/ALT) and triglycerides.
APTIVUS Indications and Usage
Aptivus(R) (tipranavir) capsules, co-administered with 200 mg of ritonavir (APTIVUS/ritonavir), is indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 24 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with APTIVUS/ritonavir:
-- The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response.
-- Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir.
-- Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding.
-- Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment.
-- Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or other underlying hepatic impairment.
-- The extensive drug-drug interaction potential of APTIVUS/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use.
-- The risk-benefit of APTIVUS/ritonavir has not been established in treatment-naïve adult patients or pediatric patients.
There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.
APTIVUS/ritonavir does not cure HIV or help prevent passing HIV to others.
Important Safety Information for APTIVUS
-- Aptivus(R) (tipranavir) capsules, co-administered with 200 mg ritonavir (APTIVUS/ritonavir), has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).
-- APTIVUS co-administered with 200 mg ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.
-- The extensive drug-drug interaction potential of APTIVUS/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use.
-- APTIVUS/ritonavir is contraindicated in patients with known hypersensitivity to any of the ingredients of the product.
-- APTIVUS/ritonavir is contraindicated in patients with moderate to severe (Child-Pugh Class B and C) hepatic insufficiency.
-- APTIVUS/ritonavir is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam due to the potential for serious and/or life-threatening events.
-- APTIVUS must be co-administered with 200 mg of ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
-- Please refer to the complete ritonavir prescribing information for a description of ritonavir contraindications and additional information on precautionary measures.
-- Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk of increased bleeding, or who are receiving medications known to increase the risk of bleeding, including supplemental high doses of vitamin E. In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir. In rats, co-administration with vitamin E increased the bleeding effects of tipranavir.
-- All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating and frequently throughout therapy with APTIVUS/ritonavir.
-- Patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Additionally, Grade 3 and 4 increases in hepatic transaminases were observed in 6% of healthy volunteers in Phase 1 studies and 6% of subjects receiving APTIVUS/ritonavir in Phase 3 studies.
-- Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation.
-- New onset or exacerbation of diabetes mellitus and hyperglycemia, and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.
-- A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of APTIVUS/ritonavir and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing's syndrome and adrenal suppression. APTIVUS/ritonavir should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk.
-- Caution should be used when prescribing sildenafil, tadalafil, or vardenafil with APTIVUS/ritonavir because concentrations of these drugs may increase. Co-administration with rifampin, St. John's wort, lovastatin, or simvastatin is not recommended. This list of medications is not complete.
-- APTIVUS should be used with caution in patients with a known sulfonamide allergy.
-- Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in patients receiving APTIVUS/ritonavir. In some, rash has been accompanied by other symptoms. In one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/ritonavir, 33% of subjects developed a rash. In Phase 2 and 3 trials, rash was observed in 14% of females and 8% to 10% of males receiving APTIVUS/ritonavir. Women using estrogens may have an increased risk of rash.
-- Treatment with APTIVUS/ritonavir has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during APTIVUS/ritonavir therapy.
-- Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. A causal relationship has not been established.
-- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS/ritonavir.
-- In clinical trials, the most frequently reported adverse reactions associated with APTIVUS/ritonavir were diarrhea, nausea, fatigue, vomiting, and headache.
Please see full Prescribing Information, including boxed WARNINGS, for APTIVUS at http://www.APTIVUS.com.
About APTIVUS
APTIVUS, a non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process.
The U.S. Food and Drug Administration (FDA) granted accelerated approval of APTIVUS on June 22, 2005. Accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses that provide meaningful benefit to patients over existing treatments. This approval is based on 24-week data from ongoing studies using surrogate endpoints. The long-term effects of APTIVUS co-administered with ritonavir (APTIVUS/r) therapy are not confirmed at this time.
APTIVUS/r is also approved in Argentina, Australia, Canada, Switzerland, Mexico, Iceland and the European Union. Most recently, APTIVUS/r received approval in Taiwan.
About Boehringer Ingelheim
Boehringer Ingelheim is committed to improving HIV therapy by providing physicians and patients with innovative antiretroviral agents.
For more information on Boehringer Ingelheim Pharmaceuticals, Inc., please visit http://us.boehringer-ingelheim.com.
References
(i) Lab Tests Online. American Association for Clinical Chemistry. Therapeutic Drug Monitoring. Available at: http://www.labtestsonline.org/understanding/analytes/thdm/glance.html. Accessed on March 27, 2007.
(ii) World Health Organization, "2006 AIDS Epidemic Update," December 2006.
Boehringer Ingelheim
http://us.boehringer-ingelheim.com
Ray