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Clinical Trials

MainTitle

Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for Disseminated Kaposi Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)

Verified September 2017 by Volkow Fernandez Patricia Amalia, National Institute of Cancerología

Sponsor
National Institute of Cancerología

Collaborator
Instituto Nacional de Enfermedades Respiratorias

Information provided by (Responsible Party)
Volkow Fernandez Patricia Amalia, National Institute of Cancerología

ClinicalTrials.gov Identifier
NCT03296553

First received: September 20, 2017
Last updated: September 28, 2017
Last Verified: September 2017
History of Changes
Purpose

Purpose

Kaposi sarcoma (KS) has an unpredictable course, patients with severe KS and low CD4 counts (<100 cells) can develop Immune Reconstitution Syndrome (IRIS) after the initiation of combined Antiretroviral Therapy (cART). The objective of this study is to evaluate the presence of IRIS and its attributable mortality in patients with HIV and severe KS with the use of Ganciclovir or the prodrug Valganciclovir prior to the initiation of cART compared with the standard management of immediate cART initiation.

Condition Intervention Phase
Kaposi Sarcoma
Human Immunodeficiency Virus
Immune Reconstitution Syndrome

Drug : Valganciclovir
Drug : Antiretroviral Combinations
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Valganciclovir for Suppression of HHV-8 Four Weeks Prior to Initiation of cART in Patients With Disseminated Kaposi Sarcoma Compare With Standard Therapy, Its Impact on the Development of IRIS and Attributable Mortality

Further study details as provided by Volkow Fernandez Patricia Amalia, National Institute of Cancerología:

Primary Outcome Measures

  • IRIS-KS-attributable mortality [ Time Frame: 24 weeks ]
    Measure mortality attributable to IRIS-KS in all the groups

Estimated Enrollment: 38
Study Start Date: October 1, 2015
Estimated Study Completion Date: October 1, 2018
Estimated Primary Completion Date: September 12, 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Valganciclovir
Oral Valgancyclovir 900 mg twice in a day during 4 weeks prior to initiation of cART (combined antirretroviral therapy) until suppression of HHV-8.
Drug: Valganciclovir

The experimental group will receive Valganciclovir 900 mg twice in a day before the initiation of cART until viral load of HHV-8 is undetectable.

Other Name: Valcyte
Active Comparator: Antiretroviral combinations
Standard treatment with cART according to current HIV Therapy Mexican guidelines.
Drug: Antiretroviral Combinations

Patients will receive standard antiretroviral treatment as recommended

Other Name: cART

Detailed Description:

Kaposi sarcoma (KS) is an angioproliferative disease associated with infection by the Human Immune Deficiency virus (HIV), mediated by cytokines, in which the presence of Human Herpes-Virus 8 (HHV-8) and immunosuppression are essential for the disease process. It has an unpredictable course and can be indolent or can entertain a progressive and fulminant disease course. Patients with severe KS can have pulmonary involvement and/or disseminated cutaneous disease and/or lymphadenopathic involvement, generally associated with low CD4 counts (<100 cells); this patients are at risk of Immune Reconstitution Syndrome (IRIS) after the initiation of cART aggravating the clinical status of the patient.
Ganciclovir and Foscarnet (antivirals) are active in vitro against HHV-8. Our work group documented, in a retrospective study with patients treated with Ganciclovir for the management of organ-end infection due to Cytomegalovirus (CMV) in the era pre-cART that they developed complete remission.
Patients with infections such as meningeal tuberculosis, cryptococcal meningitis, or CMV-related chorioretinitis, and low CD4 are at a greater risk of developing Immune Reconstitution Inflammatory Syndrome (IRIS), and, as a consequence of IRIS, of developing severe complications that cause death or irreversible sequel. In these cases, it has been demonstrated that treating the opportunistic infection and delay 4 weeks the initiation of cART; usually avoids these complications.
Objective:
To evaluate the presence of IRIS and it attributable mortality in patients with HIV and severe KS (pulmonary and/or disseminated, and/or lymphadenopathic, and/or generalized lymphedema, and/or intestinal tract compromise) with the use of Ganciclovir or the prodrug Valganciclovir prior to the initiation of cART compared with the standard management of immediate cART initiation.
Hypothesis:
Administration of Ganciclovir and the suppression of HHV-8 replication prior to administration of cART, with or without chemotherapy in patients with Acquired Immunodeficiency Syndrome (AIDS) and disseminated KS will diminish the frequency of IRIS and will exert an impact on diminishing mortality attributable to KS.
Methodology:
Open randomized clinical assay. Will include patients with AIDS and disseminated KS who accept to participate and who sign the letter of informed consent.
A disseminated case of KS is considered when it presents one or more of the following involvements: pulmonary compromise, and/or disseminated cutaneous KS, and/or lymphadenopathic and/or generalized lymphedema, and digestive tract compromise documented in at least two segments (oral cavity, esophagus, stomach, large intestine).
Exclusion criteria are patients who present another synchronic neoplasm, those receiving corticosteroids, those with replicative co-infection with hepatitis B or hepatitis C and patients with an APACHE score ≥ 15.
The study will comprise two study groups:

  1. Group 1 (randomized): Patients with HIV and disseminated KS, who will receive treatment with Ganciclovir during 4 weeks prior to initiation of cART and/or until suppression of HHV-8 or 12 weeks (whichever comes first).
  2. Group 2 (randomized): Patients with HIV and disseminated KS, who initiate standard
treatment with cART.
Sample size was calculated for a study power of 80% and an alpha of 0.05. Event rate in the control group was 40%, while that in the treated group was 5%. The number of patients in each group will be 19 for as total sample of 38 patients.
The antiretroviral scheme will be assigned according to the criteria of the "The Antiretroviral Management Guide of Persons with HIV" in effect in Mexico.
A baseline clinical evaluation will be carried out to define the extension of KS (on skin, at the gastrointestinal level by means of upper-gastrointestinal endoscopy and colonoscopy), at the pulmonary and lymphatic levels (Computerized tomography scan [CT] of the thorax and abdomen. In case of suspicion of pulmonary compromise a Gallium 67 Spect-CT Scan will be performed, in the case of suspicion of lymphadenopathic compromise; lymph node biopsy will be performed. Investigation will be conducted to document or rule out other active infections and treatment will be given if necessary including bone marrow culture.
IRIS criteria: Patients with 2 weeks of cART initiation according to their presenting one laboratory criterion and two laboratory criteria:
A reduction of at least 1 log10 of HIV-1 in viral load levels and an increase of ≥50 cells/mm3 or an increase of at least ≥2 times in the baseline levels of the CD4+ cell count
Exacerbation of KS by at least two of the following clinical criteria:
Increase in size of KS lesions Increase in number of KS lesions Appearance or exacerbation of lymphedema Appearance or increase of otherwise inexplicable pulmonary opacities in the thoracic x-ray or Computerized tomography (CT) of the thorax with negative Gallium-67 Spect-scan.
Classification of the evolution of KS:
Complete Response (CR) when all of the KS lesions disappear Partial Response (PR) when there was a diminution of >50% in number and/or size of original lesions without the appearance of new lesions Stable Disease (SD) was when there was a reduction of <50% of lesions and new lesions have not appeared Disease Progression (DP) when an increase is documented of the number and size of the KS lesions during follow-up periods Relapse when new lesions appeared in patients with CR or documented CR in previous evaluations.
Ten ml. will be obtained of anticoagulated peripheral blood with EDTA. This routine procedure will be carried out by the Attending Physician of the patients and by a qualified Phlebotomist.
At baseline and at weeks 1, 2, 4, 8, 12, 16, 24, and 48 weeks, inflammation markers will be measured related with the response of the cytosines, known in KS, such as the following: C reactive protein; D-dimer; IL-6; Il-10, Tumor Necrosis Factor (TNF) and Gamma Interferon (IFNγ). Serum and plasma will be obtained for the HIV viral load, the HHV-8 viral load, and a complete blood count will be performed, as well as the CD4 lymphocyte count, and liver function and blood chemistry tests. From the plasma samples, the absolute amount of each analyte will be quantified, and we will analyze the Luminex methodology (Bio-Rad). The plasma will be incubated with monoclonal antibody-coated spheres directed against each analyte and to a specific fluorochrome, and fluorescence will be read in Bio-Plex 2000 equipment (Bio-Rad). Absolute readings will be obtained in μg/mL for each analyte.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years to 70 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Patients will be included with AIDS naïve to antiretroviral therapy and severe KS, who accept to participate and who sign the letter of informed consent.
  • The following are the KS severity criteria: pulmonary compromise, and/or digestive tract compromise, and/or disseminated cutaneous, and/or lymphadenopathic compromise with generalized lymphedema.


Exclusion Criteria:
  • Patients with another synchronic malignant neoplasm
  • Patients receiving corticosteroids
  • Patients with active hepatitis B and/or hepatitis C
  • Patients with KS limited to skin with less than 30 lesions.
  • Patients with APACHE II score ≥15 points.

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03296553

Contacts

Contact:   Patricia Amalia Volkow Fernández, MD 015256280400 ext 12110 pvolkowf@gmail.com

Locations

Mexico
Instituto Nacional de Cancerologia Recruiting
Mexico city, Mexico, 14080
Contact: Myrna Candelaria, MD, PhD    (52)5556280400 ext 338    candelariamyrna@gmail.com
Principal Investigator: Myrna Candelaria, MD, PhD.
Sub-Investigator: Ana Ramirez, MD
Sub-Investigator: Enrique Estrada, MD

Sponsors and Collaborators

National Institute of Cancerología
Instituto Nacional de Enfermedades Respiratorias
More Information

More Information


Responsible Party: Volkow Fernandez Patricia Amalia, Infectious disease consultant, Clinical Professor, National Institute of Cancerología  
ClinicalTrials.gov Identifier: NCT03296553   History of Changes  
Other Study ID Numbers: (015/031/INI) (CEI/950/15)  
Study First Received: September 20, 2017  
Last Updated: September 28, 2017  

Additional relevant MeSH terms:
Sarcoma
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Sarcoma, Kaposi
Immune Reconstitution Inflammatory Syndrome
Valganciclovir
Ganciclovir

ClinicalTrials.gov processed this data on October 18, 2017
This information is provided by ClinicalTrials.gov.