Clinical trial NCT03296553
Conditions: Kaposi Sarcoma Human Immunodeficiency Virus Immune Reconstitution Syndrome
Sponsor: National Institute of Cancerología
Start date: 2015-10-01; Completion date: 2019-08-26
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Kaposi sarcoma (KS) has an unpredictable course, patients with disseminated KS starting combined Antiretroviral Therapy can develop Immune Reconstitution Syndrome (IRIS), with a severe clinical presentation and high mortality (severe-IRIS-KS). The objective of this study is to evaluate the presence of Severe IRIS-KS and it´s attributable mortality in patients with AIDS and disseminated KS with the use of valganciclovir prior to the initiation of cART compared with the standard management of immediate cART initiation.

Detailed description:
Kaposi sarcoma (KS) is a Human Herpes-8 disease, it has been described as an angioproliferative disease mediated by cytokines in an environment of immunodeficiency and thus associated with HIV infection. Its course has been described as unpredictable; it can be indolent or can be progressive with a fulminant course. Patients with disseminated KS can have an extensive disseminated cutaneous disease with lymphedema and/or lymph node, gastrointestinal or pulmonary involvement, usually associated with low CD4 T cell counts (\<100 cells).

High early mortality in patients starting cART has been described in different settings, and it has been attributed to the development of Immune Reconstitution Syndrome KS (IRIS-KS).

In patients developing IRIS-KS the clinical event until now recognized as IRIS-KS: increase in KS lesion, lymphedema or pleural effusion that is associated with CD4 cells increase and the decrease of at least one log of HIV VL does not fully express what threatens patients life. The clinical picture of IRIS-KS that threatens the patient's life is the abrupt development of fever with no other infection recognized, rapid clinical deterioration with thrombocytopenia, anemia, hyponatremia, and hypoalbuminemia together with an increase in KS lesion, lymphedema, or pleural effusion, this clinical picture we have named Severe-Iris-KS.

Patients with AIDS and disseminated KS are at risk of developing severe Immune Reconstitution Syndrome KS (S-IRIS-KS) after the initiation of cART and this has been associated with high mortality.

Ganciclovir and Foscarnet (antivirals) are active in vitro against HHV-8; valganciclovir is a prodrug of ganciclovir, it is an oral formulation.

Our group documented, in a retrospective study that patients that were treated with ganciclovir for the management of Cytomegalovirus (CMV) end-organ disease in the pre-cART era achieve KS complete remission.

Patients with infections such as meningeal tuberculosis, cryptococcal meningitis, or CMV-related chorioretinitis, are also at a greater risk of developing IRIS, and as a consequence of it, deteriorate their clinical conditions that can even lead to death or irreversible sequel. In these cases, it has been demonstrated that starting treatment for the opportunistic infection and delays two or four weeks cART initiation; is possible to avoid or diminish these complications.

Objective:

To evaluate the occurrence of S-IRIS-KS and it attributable mortality in patients with HIV and disseminated KS (pulmonary and/or disseminated, and/or lymphadenopathic, and/or generalized lymphedema, and/or intestinal tract compromise) with the use of valganciclovir (ganciclovir prodrug, oral formulation) prior to the initiation of cART compared with the standard management of immediate cART initiation.

Hypothesis:

In patients with AIDS and disseminated KS administration of valganciclovir as an anti-HHV-8 agent can diminish viral replication prior to administration of cART, and thus decrease the frequency of S-IRIS-KS and will exert an impact on diminishing S-IRIS-KS attributable mortality.

Methodology:

Open randomized clinical assay. Will include patients with AIDS and disseminated KS who accept to participate and sign informed consent.

Inclusion criteria:

Patients \>18 years old, HIV+ naïve to cART with DKS, able and willing to provide written informed consent.

DKS was defined as the presence of KS pulmonary disease and/or ≥30 KS skin lesions, with or without lymphedema, and/or lymph node involvement, and/or GIT KS involvement (biopsy-proven at least in one site).

Exclusion criteria:

Another concomitant malignancy, Multicentric Castleman Disease (MCD), steroid treatment two months prior to screening, active HBV or HCV or CMV end-organ disease, or severely ill patients with APACHE II score \>15.

The study will comprise two study groups:

1. Group 1:Patients will receive treatment with valanciclovir during 4 weeks prior to initiation of cART and/or continue for 48 weeks
2. Group 2: Patients will initiate standard treatment with cART. Both groups recieve bleomycin/vincristine; according to treating physician.

Randomization Patients will be randomized by blocks of ten; the assigned group written in closed envelopes: either to Experimental Group 1 (EG) to receive valganciclovir 900 mg twice daily for 48 weeks and initiate cART at week 4 after randomization.

Or to the Control Group 2(CG) to start cART immediately according to current Mexican Guidelines.

Blinding:

No blinding was considered feasible for personnel or patients; this is an open label study.

Sample Size Sample size was calculated for a study power of 80% and an alpha of 0.05. Event rate in the control group was estimated as 40%, while that in the treated group was considered 5%. The number of resulting patients in each group is 19 for as total sample of 38 patients. This assumes a significant impact of treatment impact on S-IRIS occurrence and its mortality.

The antiretroviral scheme will be assigned according to the criteria of the "The Antiretroviral Management Guide of Persons with HIV" in effect in Mexico.

Candidates will have an initial thorough clinical evaluation including a work-up to diagnose coinfections and rule out other neoplasms that comprise: ophthalmologic evaluation, computed tomography (CT) scan (neck, thorax, and abdomen), bone marrow culture with bone biopsy, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) serology, venereal disease research laboratory (VDRL) test and if indicated lumbar puncture to rule-out neurosyphilis, Histoplasma urinary antigen and serology, and GenXpert MTB/RIF test. Upper gastrointestinal tract (GIT) endoscopy with biopsy of lesions; colonoscopy will be performed only on patients with diarrhea or lower-GIT bleeding. Biopsies of enlarged lymph nodes will be obtained and process for histopathological analysis and culture. If indicated, bronchoscopy with bronchoalveolar lavage (BAL) will be performed as well as a thoracic Gallium 67 Spect-CT Scan or PET-FDG scans.

Criteria for Non-svere-IRIS KS and Severe-IRIS-KS

Non-severe-IRIS-KS: si defined as an increase in the number of KS lesions plus ≥one log10 of HIV-1 RNA VL decrease or ≥50 cells/mm3 or ≥2-fold from baseline CD4+ cells increase after cART initiation.

Severe -IRIS-KS is defined as an abrupt clinical deterioration after cART initiation alongside the presence of at least two clinical and at least three laboratory criteria.

Clinical criteria: 1) Fever (no identified concomitant infection), 2) increase in the size or number of KS lesions, 3) exacerbation of lymphedema, 4) appearance or increase of otherwise unexplained lung opacities on the chest images with a negative Gallium-Scan negative and 4) appearance or increase of pleural effusion.

Laboratory criteria: 1) Thrombocytopenia \<100,000 platelets/ml; 2) Anemia (decrease of at least 1 g/dl from previous measure and no obvious bleeding), 3) Hyponatremia \<135 mEq/L and 4) Hypoalbuminemia \<3.5 g/dL. This is the clinical picture associated with death.

Classification of KS evolution:

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.

Visits will be performed at baseline, week 1, 2, 4, 8, 12, 16, 24, and 48. At each visit, an Infectious Diseases specialist will perform a clinical evaluation, and pictures of skin lesions will photograph. Blood samples will be obtained for: WBC count, complete blood chemistry, urine analysis, CRP, D-Dimer, HIV VL with Abbott Real-time, HHV-8, CMV, and Epstein-Barr Virus (EBV) VL ELITe MGB KIT by ELITe InGenius Software, CD4+ and CD8+ cells count and percentage, (flow cytometry, Facs Canto II, Becton Dickinson) CD4/CD8 ratio and plasma levels of interleukin 6, 10 (IL-6, IL-10), tumor necrosis factor (TNF) and interferon-gamma (IFN-ɤ) were measured using a sandwich-type immunoassay, ELISA (Biolegend). Serology for syphilis, HBV, and HCV will be repeat at week 24 and 48. If patients had an exacerbation of KS outside the scheduled visit they will be reevaluated with laboratory tests and study images.

A qualified phlebotomist will carry out blood sampling.

Primary outcome:

Mortality by all causes at end of follow-up, 48 weeks, adjusted at least by age, gender, CD4, and viral load of HV8, primarily with a survival analysis by a Cox regression, but also with a logistic regression model.

Secondary outcomes:

Total number of SIRI events (S-IRIS-KS and Non-S-IRIS-KS) in treated and control group. This is going to be done by a Poisson´s models analysis adjusted by age, gender, coinfections, basleine: CD4, and viral load of HV8, C reactive protein, HIV VL, IL6, IL10, TNF, and IFN. We will compare mortality in patients with pulmonary KS between groups.

Vigilance of adverse events:

Adverse events in treated and control group.

Statistical analysis:

The primary analysis is going to be as intention to treat, but as a secondary analysis also as per protocol analysis is going to be performed for mortality, and Severe-IRIS. KS..

Ethical issues:

Protocol and informed consent were reviewed and accepted by IRB form Intsituto Nacional de Cancerología. CEI/950/15No.15/03/INI) First submission: 14 October 2014 First amendment: July 22, 2016 Second amendment. 25 April 2018

Arms: arm 1: Oral Valgancyclovir 900 mg twice in a day during 4 weeks prior to initiation of cART (combined antirretroviral therapy) until suppression of HHV-8. arm 2: Standard treatment with cART according to current HIV Therapy Mexican guidelines.
Interventions: intervention 1: Valganciclovir intervention 2: Antiretroviral Combinations
Intervention descriptions: intervention 1: 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. intervention 2: Patients will receive standard antiretroviral treatment as recommended

Protocol documents:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
TITLE: 
 
Valganciclovir Four Weeks Prior to cART Initiation Compared to Standard Therapy for 
Disseminated Kaposi Sarcoma 
 
 
NCT NUMBER: NCT03296553 
 
DATE: July 14, 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 


INFORMED CONSENT 
 
 
We invite you to participate in a clinical research study. Your participation in this study is 
completely voluntary. No one can force you to participate. If you decide not to participate, nor will 
it change the medical care to which you are entitled at the National Cancer Institute. Before 
deciding whether or not to participate, please read this consent letter carefully and ask any 
questions you may need to resolve any concerns you may have. At the end of this letter of consent 
is a list of the rights of people involved in research. 
 
Once you understand what this study means, you can decide whether or not to participate. If you 
agree to participate, you will have to sign and date this informed consent letter. 
 
Kaposi's sarcoma is considered a type of cancer associated with AIDS, and it is caused by another 
virus called human herpes-virus 8 or Kaposi's sarcoma virus (HVH-8). Infection with the Human 
Immunodeficiency Virus (HIV) favors the development of Kaposi's sarcoma. 
 
Currently the treatment for Kaposi's sarcoma is multiple antiretroviral drugs against HIV, called 
highly active antiviral treatments (HAART). These HAART schemes prevent the virus from 
multiplying in the body and this allows patients to improve their defenses destroyed by HIV (CD4 
lymphocytes increase their number). 
 
However, in patients who arrive with very low CD4 levels (less than 100), the initiation of HAART 
may cause a worsening in some patients who have another active infection such as tuberculosis, 
tuberculous meningitis or infection of the retina by Cytomegalovirus (this is a virus of the herpes 
virus family that affects patients with a very altered defense system). 
 
It is complex to understand, but the deterioration is caused because the individual's defenses 
improve in response to HAART and as there are more defense cells they cause greater 
inflammation and this damages the affected organs. For this reason, management protocols have 
been designed where the infection is initially treated and the onset of HAART is delayed for at 
least two weeks or until the inflammation in the retina, meninges or in any other organ has 


decreased. This makes it possible to avoid these serious consequences in most patients. In 
patients with Kaposi's sarcoma that affects the lung, and / or lymph nodes or who have more than 
30 skin lesions. This phenomenon has also been described with worsening of the lesions when 
HAART is started. 
 
This study aims to see if it is possible to prevent the worsening of the lesions of disseminated 
Kaposi Sarcoma, if the patient is first treated with an antiviral drug that has activity against the 
human herpes virus 8 (HHV-8), the causative agent of sarcoma of Kaposi. 
 
Objectives of the study 
 
We want to compare two types of treatment: one group of patients will be treated according to 
current standards with HAART and if necessary chemotherapy based on bleomycin and vincristine, 
and a second group will first receive ganciclovir or valganciclovir, the treatment for HVH- 8, and 
HAART will start when the HHV-8 viral load in the blood has significantly decreased. This group will 
also receive chemotherapy with bleomycin and vincristine if required. 
 
The assignment to which group you will enter is done by lottery, which is appropriate since it is not 
known at this time which of the 2 treatments is preferable. You yourself will take out the paper 
that will be assigned to you and no one from the research group will have access or will be able to 
change the group that will be assigned to you in the draw. 
 
Study procedures 
If you are eligible and agree to participate, you will sign and date this consent letter. 
 
Patients with a diagnosis of HIV and severe Kaposi Sarcoma will be included according to the 
following criteria: generalized lymphedema (swelling of all or several parts of the body, for 
example legs and face), and / or more than 30 Kaposi Sarcoma lesions in the skin, and / or that 
there are Kaposi Sarcoma lesions in the digestive tract visualized by means of an endoscopy study, 
or suspicion of Kaposi Sarcoma lung involvement by computed tomography study or / and some 
nuclear medicine study such as PET when it is suspected that his lymph nodes are affected by this 
disease or scintigraphy with Gallium when it is suspected that the lung is affected. 


 
Your doctor will take a complete medical history and physical examination and you will be asked 
for a series of studies, most will have to be done even if you are not participating in the study in 
order to evaluate you properly. An initial evaluation will be performed to define the extent of 
Kaposi's sarcoma, including:  
 
Number and documentation by photography of the skin lesions, with biopsy and 
histopathological report of Kaposi's Sarcoma. 
 
Blood sample for laboratory tests, including CD4 cells and HIV viral load. 
 
Performing endoscopy of the stomach and esophagus with taking a biopsy of suspicious 
lesions of Kaposi Sarcoma. 
 
Performing endoscopy of the large intestine with taking a biopsy of suspicious lesions of 
Kaposi's Sarcoma. 
 
Tomography (CT) of the chest only when it is suspected that the lung is affected by 
Kaposi's Sarcoma or some other related disease such as tuberculosis or others. 
 
PET in case the lymph nodes are suspected of being affected by Kaposi's sarcoma. 
 
The presence of other infectious diseases such as syphilis, tuberculosis, toxoplasmosis, 
cytomegalovirus, and hepatitis will be searched extensively. These are procedures that are 
performed on patients even if they do not enter the study. For this, the following will be 
measured: basal serum VDRL and antitreponemal antibodies (blood) (to investigate syphilis). In 
those patients with positive VDRL, a lumbar puncture should be performed to extract 
cerebrospinal fluid and perform VDRL on it. Profile of viral hepatitis B and C (blood). Basal 
toxoplasma serologies (blood). Cryptococcal serum antigen in patients with less than 100 CD4 
(blood). 
Only in those cases with lung lesions, bronchoscopy, bronchi alveolar lavage will be performed 
(this study consists of introducing a thin flexible tube that allows visualizing the interior part of the 
lung and injecting water, which is later recovered to order study) and taking a lung biopsy at the 
discretion of the researcher. 
 
The identification of any opportunistic disease will receive the appropriate treatment stipulated by 
the management guidelines. 


They will be measured at baseline (the day the study begins) and at weeks 1, 2, 4, 8, 12, 16, 24, 
and 48 markers of inflammation related to the response of cytosines (they are substances that are 
produced in the body when there is inflammation and are described below) known in Kaposi's 
Sarcoma, to assess the inflammatory status of the patient, such as: Viral load for HHV-8, C-reactive 
protein, D-dimer, IL-6, Il- 10, TNF (blood). 
 
Assessment by the ophthalmologist (eye specialist) at the baseline visit, at 2 and 4 weeks and 
thereafter at the discretion of the ophthalmologist. 
 
To obtain the samples, a vein will be punctured in your arm, as is usual. All these tests would be 
done to you if the treating doctor so considered it even if you decide not to participate in the 
study, except for taking blood for viral load of HHV-8, IL-6, IL-10 and TNF. 
  
The results of all these tests may take a few days, but you will be informed of all of them as the 
results are available. A total of 38 patients distributed in each group of 19 people will be included. 
 
Risks and discomforts 
The disease that you suffer from is serious and your life is at risk regardless of the medical 
interventions to try to help you, it is hoped to reduce this risk but only in the course of the 
investigation will we know if this risk was reduced with the proposed treatment. The tests to 
which you will be submitted involve some discomfort, all these procedures would be done for the 
management of your disease regardless of your participation in the study. 
 
Your doctor will do everything possible to lessen the discomfort and will be attentive to any 
problems. It is important for you to understand that whether you participate in the study or not, 
these tests are important to your health and your doctor would recommend them anyway. 
 
Benefits of participation 
The procedures to be done in this study are the same as if you were not in the study. However, 
with your participation, you can help increase medical knowledge, which could help other patients 
with the same disease in the future. 
 


Compensation and costs 
 
You will not be paid anything for your participation in the study. In the event of a health problem 
arising from your participation in the study, you will receive medical care at no cost to you at 
INCan. Also, all tests will be done at no cost to you. 
 
The tests related to this study will be done at no cost to you and will be provided to you. free 
administration of ganciclovir or vagnacilcovir in the corresponding case and the payment of the 
medications that are required for the management of adverse events related to the use of two 
medications such as the colony stimulating factor in case of low white blood cells . You will receive 
antiretrovirals through the universal access program that corresponds to your place of residence 
and will be processed by the INCan Infectious Diseases group. Participation in the study does not 
imply the administration of other drugs not related to Kaposi Sarcoma and its treatment or the 
free provision of other services by INCan. 
 
Responsibilities of the subject 
You will need to go to study visits, follow the instructions your doctors give you, and take the 
study drug as directed. 
 
You should not participate in any other study while you are in this one. 
 
Confidentiality 
Your participation in this study will be recorded in your medical record, but will not be disclosed. 
Researchers, members of the ethics committee that approved the study, and representatives of 
health authorities may have access to your medical record for verification purposes. If the results 
of the study are published, it will be in a scientific journal and you will not be identified by name. 
 
Contact persons 
If you have questions about this study, or if you think you have been injured as a result of it, please 
contact Dr. Patricia Volkow 554747-1020 ext. 12110. 
 


If you have questions about your rights as a participant in research, please contact Dr. Myrna 
Gloria Candelaria Hernández of the Research Ethics Committee of the National Cancer Institute or 
Dr. Alejandra Monroy López 56280400 extension 37015, regarding For any technical aspect of the 
study that will be carried out, contact Dr. Patricia Volkow 47471020 extension 12110 or the cell 
phone 5560989351. 
 
CONSENT 
 
I have read and understand the above information about this study. I have been able to ask 
questions, which have been answered to my satisfaction. I understand that my participation is 
voluntary, and that I may refuse to participate or leave the study at any time, without prejudice to 
myself or my health care rights. I freely agree to participate in the study. I will receive a signed 
copy of this informed consent letter. 
 
 
 
Participant Name 
Signature 
Date 
 
 
 
 
Name who obtained consent signature 
Signature 
Date 
 
 
 
 
Witnes #1 Name 
Signature 
Date  
 
 
Witnes 2 Name 
Signature 
Date  
 
 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE: 
 Valganciclovir Four Weeks Prior to cART Initiation Compared to 
Standard Therapy for Disseminated Kaposi Sarcoma 
 
 
NCT NUMBER: NCT03296553 
 
DATE : JULY 23, 2015. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STUDY PROTOCOL 
 
Objective: 
To evaluate the occurrence of severe immune reconstitution inflammatory syndrome 
associated to Kaposi Sarcoma (S-IRIS –KS) and it´s attributable mortality in patients with 
AIDS and disseminated KS (dKS) (pulmonary and/or skin disseminated, and/or 
lymphadenopathic, and/or generalized lymphedema, and/or gastrointestinal tract 
involvement) with the use of valganciclovir  (ganciclovir prodrug, oral formulation) prior to 
the initiation of combined antiretroviral therapy (cART) compared with the standard 
management of immediate cART initiation. 
 
Hypothesis: 
In patients with AIDS and disseminated KS administration of valganciclovir as an anti-HHV-
8 agent can diminish viral replication prior to administration of cART, and thus decrease 
the frequency of S-IRIS-KS with a subsequent reduction on S-IRIS-KS attributable mortality.  
 
Methodology: 
Open randomized clinical assay. Will include patients with AIDS and disseminated KS who 
accept to participate and sign informed consent.  
  
Inclusion criteria:   
Patients >18 years old, HIV+ naïve to cART with dKS, able and willing to provide written 
informed consent.  
DKS was defined as the presence of KS pulmonary disease and/or ≥30 KS skin lesions, with 
or without lymphedema, and/or lymph node involvement, and/or gastrointestinal tract KS 
involvement (biopsy-proven at least in one site).  
 
Exclusion criteria:   
Another concomitant malignancy, Multicentric Castleman Disease (MCD), steroid 
treatment two months prior to screening, active Hepatitis B, Hepatitis C  or CMV end-
organ disease infection, and/or severely ill patients with APACHE II score >15 points. 
 
The study will comprise two study groups: 
1. 
Group 1: Patients will receive treatment with valganciclovir during 4 weeks prior to 
initiation of cART and/or continue for 48 weeks 
2. 
Group 2: Patients will initiate standard treatment with cART.  
Both groups receive chemotherapy with bleomycin/vincristine; according to treating 
physician.  
 
Randomization 
Patients will be randomized by blocks of ten; the assigned group written in closed 
envelopes:  
Experimental Group 1 (EG) will receive valganciclovir 900 mg twice daily for 48 weeks and 
initiate cART at week 4 after randomization. 


Control Group 2 (CG) will start cART immediately according to current Mexican Guidelines. 
 
Blinding: 
No blinding was considered feasible for personnel or patients; this is an open label study.  
 
Sample Size 
Sample size was calculated for a study power of 80% and an alpha of 0.05. Event rate in 
the control group was estimated as 40%, while that in the treated group was considered 
5%. The number of resulting patients in each group is 19 for as total sample of 38 patients.  
This assumes a significant impact of treatment impact on S-IRIS-KS occurrence and its 
mortality.   
 
The antiretroviral scheme will be assigned according to the criteria of the “The 
Antiretroviral Management Guide of Persons with HIV” in effect in Mexico. 
 
Candidates will have an initial thorough clinical evaluation including a work-up to diagnose 
coinfections and rule out other neoplasms that comprise: ophthalmologic evaluation, 
computed tomography (CT) scan (neck, thorax, and abdomen), bone marrow culture with 
bone biopsy, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) serology, venereal 
disease research laboratory (VDRL) test and if indicated lumbar puncture to rule-out 
neurosyphilis, Histoplasma urinary antigen and serology, and GenXpert MTB/RIF test.  
Upper gastrointestinal tract (GIT) endoscopy with biopsy of lesions; colonoscopy will be 
performed only on patients with diarrhea or lower-GIT bleeding. Biopsies of enlarged 
lymph nodes will be obtained and process for histopathological analysis and culture. If 
indicated, bronchoscopy with bronchoalveolar lavage (BAL) will be performed as well as a 
thoracic Gallium 67 Spect-CT Scan or PET-FDG scans.  
 
Criteria for Non-severe-IRIS KS and Severe-IRIS-KS 
 
Non-severe-IRIS-KS: Is defined as an increase in the number of KS lesions plus ≥one log10 
of HIV-1 RNA VL decrease or ≥50 cells/mm3 or ≥2-fold from baseline CD4+ cells increase 
after cART initiation.  
 
Severe-IRIS-KS: Is defined as an abrupt clinical deterioration after cART initiation 
alongside the presence of at least two clinical and at least three laboratory criteria.  
Clinical criteria:  1) Fever (no identified concomitant infection), 2) increase in the size or 
number of KS lesions, 3) exacerbation of lymphedema, 4) appearance or increase of 
otherwise unexplained lung opacities on the chest images with a negative Gallium-Scan 
negative and 4) appearance or increase of pleural effusion. 
Laboratory criteria:  1) Thrombocytopenia <100,000 platelets/ml; 2) Anemia (decrease of 
at least 1 g/dl from previous measure and no obvious bleeding), 3) Hyponatremia <135 
mEq/L and 4) Hypoalbuminemia <3.5 g/dL.  This is the clinical picture associated with 
death. 
 


Classification of KS evolution: 
 
Complete Response (CR): when all of the KS lesions disappear, according to physician´s 
criteria documented by pictures taken in each visit.  
Partial Response (PR): when there was a diminution of >50% in number and/or size of 
original lesions without the appearance of new lesions, according to physician´s criteria 
documented by pictures taken in each visit. 
Stable Disease (SD): was when there was a reduction of <50% of lesions and new lesions 
have not appeared, according to physician´s criteria documented by pictures taken in each 
visit. 
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. 
 
Visits will be performed at baseline, week 1, 2, 4, 8, 12, 16, 24, and 48. At each visit, an 
Infectious Diseases specialist will perform a clinical evaluation, and pictures of skin lesions 
will photograph. Blood samples will be obtained for: WBC count, complete blood 
chemistry, urine analysis, CRP, D-Dimer, HIV VL with Abbott Real-time, HHV-8, CMV, and 
Epstein-Barr Virus (EBV) VL ELITe MGB KIT by ELITe InGenius Software, CD4+ and CD8+ 
cells count and percentage, (flow cytometry, Facs Canto II, Becton Dickinson) CD4/CD8 
ratio and plasma levels of interleukin 6, 10 (IL-6, IL-10), tumor necrosis factor (TNF) and 
interferon-gamma (IFN-ɤ) were measured using a sandwich-type immunoassay, ELISA 
(Biolegend). Serology for syphilis, HBV, and HCV will be repeated at week 24 and 48. If 
patients had an exacerbation of KS outside the scheduled visit they will be reevaluated 
with laboratory tests and study images.  
A qualified phlebotomist will carry out blood sampling. 
 
 
Primary outcome: 
Mortality by all causes at end of follow-up, 48 weeks, adjusted at least by age, gender, 
CD4, and viral load of HHV-8, primarily with a survival analysis by a Cox regression, but 
also with a logistic regression model.   
 
Secondary outcomes: 
Total number of SIRI events (S-IRIS-KS and Non-S-IRIS-KS) in treated and control group.  
This is going to be done by a Poisson´s models analysis adjusted by age, gender, 
coinfections, basleine: CD4, and viral load of HV8, C reactive protein, HIV VL, IL6, IL10, 
TNF, and IFN. We will compare mortality in patients with pulmonary KS between groups. 
 
 
Vigilance of adverse events: 
Adverse events in treated and control group will be reported. 
 


Statistical analysis: 
The primary analysis is going to be as intention to treat, but as a secondary analysis also as 
per protocol analysis is going to be performed for mortality, and S-IRIS-KS. 
 
 
Ethical issues: 
Protocol and informed consent were reviewed and accepted by IRB form Instituto 
Nacional de Cancerología. (CEI/950/15No.15/03/INI) 
First submission: 14 October 2014  
First amendment:  July 22, 2016 
Second amendment.  25 April 2018 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
TITLE: Valganciclovir Four Weeks Prior to cART 
Initiation Compared to Standard Therapy for 
Disseminated Kaposi Sarcoma 
 
NCT number: 03296553 
 
DATE: November 30, 2019.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Statistical analysis 
 
 
Sample size was calculated for a study power of 80% and an alpha of 0·05, with an  
estimated event rate (IRIS) in the control group of 40%, and in the treated group of 5%.  
The number estimated in each group was 19, for a total sample of 38 patients.   
 
Descriptive statistics were performed, including the number of deaths, and episodes of S- 
IRIS-KS, in the CG and EG groups. Comparisons between EG and CG were performed, as 
intention-to-treat (ITT), and as per-protocol analysis, for the primary outcome of mortality 
attributed to S-IRIS-KS using Proportional-Hazard Cox models.  
 
In addition, we compared the impact of treatment on repeated episodes of S-IRIS-KS by  
multivariate Poisson model and by the number of participants with at least one S-IRIS-KS  
event, as repeated events can occur in the same patient, and the total number of events  
may be due to a few very susceptible individuals.  
 
Statistical models were adjusted by baseline CD4+, CD4+/CD8+ cell ratio, HHV-8 and HIV  
VL, plasmatic IL-6, CRP and by the presence of concomitant coinfections. Analyses were  
performed using Stata Statistical program.