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This study will address HIV patients who are on antiretroviral treatment (ART) and experiencing immunological failure. The cause of immunological failure in HIV patients could be due to several factors such as age, gender, Cluster of Differentiation (CD4)+ count before started treatment and some inflammation in the gut. The C-C Chemokine Receptor 5 (CCR5) receptor on T lymphocyte CD4+ are abundantly found in the gut and attacked by HIV virus during acute infection causing irreversible damage.
The disruption of gut integrity and chronic inflammation further causing translocation of bacteria in gut lumen to the blood. Thus resulting persistent low CD4+ or immunological failure.
This evaluation plan is designed to establish the role of investigation product (probiotics) to improve gut inflammation in HIV patients.
HIV patients could develop immunological failure despite being treated with antiretroviral therapy (ART). Thus resulting the increase of morbidity and mortality among HIV patients, especially in Indonesia. The immunological failure is associated with decreased gut integrity and immunity, increased gut inflammation, and gut bacterial translocation to the blood. Memory CD4+ T cell damage in gut associated lymphoid tissue (GALT) by HIV-1 virus leads to decreased production of Th17 in gut mucosal layer. Furthermore, low level of Th17 facilitates bacterial translocation in HIV patients.
Probiotic supplementation (Lactobacillus) could decrease the gut inflammation in some diseases including HIV infection; thus helps increasing the gut integrity and immunity by repairing the gut mucosal tight junction, increasing mucin production, and regulating gut Th17. As a result, the gut inflammation and bacterial translocation decreases. Nevertheless, the benefit in HIV patients with immunological non responder status has not been established.
The investigators plan to perform double blind randomized clinical trial of probiotics (containing Lactobacillus plantarum, Streptococcus thermophiles, Bifidobacterium bifidum) in HIV patients with immunological non responder status. The Subject who fulfill inclusion criteria, willing to participate and sign informed consent will be randomized into two groups: the group receiving probiotics (n=40) and the group of placebo (n=40). Intervention will be held for 12 weeks. This study will evaluate the gut mucosal integrity and immunity by Th17 measurement; bacterial translocation by 16S ribosomal RNA (16S RNA) measurement; and gut inflammation by fecal calprotectin measurement before and after the intervention. Moreover, the investigators will measure the CD4+ level to assess immune status recovery before and after the intervention. Side effects, HIV symptom index, Food Frequency Questionnaire will also be assessed every 4 weeks.
Statistical analysis will uses: paired and independent t test (if normally distributed) or using Wilcoxon and Mann Whitney test (if not normally distributed). HIV symptom index and Food frequency will be reported descriptively.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Probiotics Rillus® | Experimental | Rillus®, Chewing tablet containing viable cell 1.0 x 10^9 colony forming unit (Lactobacillus plantarum 8.55 mg, Streptococcus thermophilus 8.55 mg, Bifidobacterium bifidum 2.55 mg, fructooligosaccharide 480 mg), isomalt, xylitol, milk flavour, vanilla flavour Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks |
|
| Placebo | Placebo Comparator | Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rillus® | Drug | Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| CD4+ Level | CD4 level in blood (cell/μL) indicate immune status of patient receiving probiotics or placebo, measure between baseline and at 12 weeks of intervention. Analysis will include CD4 T cell levels after intervention, adjusted with duration of ARV therapy and baseline CD4 levels, as well as unadjusted. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Th17 Level Change | Change in Th17 level in blood to assess improvement of gut mucosal integrity and immunity between baseline and at 12 weeks, measured in cell/μL The results was divided in to unadjusted and adjusted Th17 level change. | 12 weeks |
| 16S Ribosomal RNA (rRNA) Total |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Food Frequency | Food Frequency Questionnaire (FFQ): A questionnaire consisted of food and drink list and frequency to assess patients' dietary pattern in the past one week. Nutritionist will be asking the participants for the questionnaire questions. The food frequency scaled to "more than one time daily", "once daily", "3-6 times in one week", "1-2 times in one week", "less than one time in one week", "never". We assessed changes in tempeh consumption (as part of FFQ question) after the 12-week intervention by categorizing participants into two groups based on their post-intervention intake: 'seldom' (consuming tempeh 1-2 times per week) and 'often' (consuming tempeh daily). The number of participants in each category was then recorded. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Erni J Nelwan, MD, PhD | Indonesia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| HIV Clinic, Cipto Mangunkusumo Hospital | Jakarta | 10430 | Indonesia |
Eligible patient was offered and signed informed consent while agree to participate. Total of 1771 patients visited POKDISUS. Completed data was available for 111 patients and 80 patients gave informed consent to participate.
Study recruitment was done between May and August 2018, study observation was done for 90-day for each subject and completed in October 2018. During study period patient was recruited consecutively on the day of policlinic visit by evaluate the existing medical record data included (1) data of CD4+ T cell and (2) viral load data at least one year ago (3) using ARV for at least 6-month.
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| ID | Title | Description |
|---|---|---|
| FG000 | Probiotics Rillus® | Rillus®, Chewing tablet containing viable cell 1.0 x 10^9 colony forming unit (Lactobacillus plantarum 8.55 mg, Streptococcus thermophilus 8.55 mg, Bifidobacterium bifidum 2.55 mg, fructooligosaccharide 480 mg), isomalt, xylitol, milk flavour, vanilla flavour Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Rillus®: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
| FG001 | Placebo | Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Placebo: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Probiotics Rillus® | Rillus®, Chewing tablet containing viable cell 1.0 x 10^9 colony forming unit (Lactobacillus plantarum 8.55 mg, Streptococcus thermophilus 8.55 mg, Bifidobacterium bifidum 2.55 mg, fructooligosaccharide 480 mg), isomalt, xylitol, milk flavour, vanilla flavour Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Rillus®: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | CD4+ Level | CD4 level in blood (cell/μL) indicate immune status of patient receiving probiotics or placebo, measure between baseline and at 12 weeks of intervention. Analysis will include CD4 T cell levels after intervention, adjusted with duration of ARV therapy and baseline CD4 levels, as well as unadjusted. | The results was divided in to unadjusted and adjusted CD4 level change | Posted | Median | 95% Confidence Interval | cell/μL | 12 weeks |
|
12 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Probiotics Rillus® | Rillus®, Chewing tablet containing viable cell 1.0 x 10^9 colony forming unit (Lactobacillus plantarum 8.55 mg, Streptococcus thermophilus 8.55 mg, Bifidobacterium bifidum 2.55 mg, fructooligosaccharide 480 mg), isomalt, xylitol, milk flavour, vanilla flavour Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Rillus®: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | Constipation | Non-systematic Assessment |
This study did not assess the viability of probiotics which were administered through the evaluation of the storage during this study.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr dr. Erni Juwita Nelwan, Ph.D, Sp.PD-KPTI | Tropical and Infectious Disease Division, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia-Cipto Mangunkusumo Hospital, Indonesia | +62811961229 | ejnelwan@yahoo.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol and Statistical Analysis Plan | May 1, 2018 | Feb 15, 2024 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form: Informed Consent Form | Oct 30, 2017 | Jun 28, 2019 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| D035061 | Control Groups |
| ID | Term |
|---|---|
| D015340 | Epidemiologic Research Design |
| D004812 | Epidemiologic Methods |
| D008919 | Investigative Techniques |
| D012107 | Research Design |
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double blind placebo control study
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|
| Placebo | Other | Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
|
|
Total of 16SrRNA of translocated gut bacteria in blood, measured in copies/mL, presented as median and interquartile range. |
| 12 weeks |
| Fecal Calprotectin Level Change | Change in calprotectin level in feces to assess gut inflammation between baseline and at 12 weeks, measured in μg/g. The results was divided in to unadjusted and adjusted fecal calprotectin level change | 12 weeks |
| Amount of Participants With HIV Related Symptoms | A questionnaire called HIV Symptoms Index (Have been validated in Indonesian language) containing self administered 20 questions consisted of 15 somatic and 5 psychological symptoms to assess Human Immunodeficiency Virus (HIV) related symptoms in patients. The total score is calculated by summing the numbers of each symptom (0 = no symptoms, 1 = no disturbing symptoms, 2 = there are symptoms that are a little annoying, 3 = there are disturbing symptoms, 4 = there are very disturbing symptoms), with a minimum score of 0 and maximum 80. Somatic symptoms range from 0-60 and psychological symptoms range from 0-20. An increase in score indicates a worsening condition. Change in HIV Symptoms Index score to assess improvement of somatic and psychological symptoms between baseline and at 12 weeks. The results was divided into somatic and psychological symptoms. Both of them were divided again into unadjusted and adjusted HIV Symptoms Index score Change. | 0,4,8,12 weeks |
| 0,4, 8, 12 weeks |
| BG001 | Placebo | Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Placebo: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Th17 Level | Median | Inter-Quartile Range | cell/μL |
|
| CD4+ level | Median | Inter-Quartile Range | cell/μL |
|
| Fecal Calprotectin Level | Median | Inter-Quartile Range | μg/g |
|
| OG001 | Placebo | Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Placebo: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. |
|
|
|
| Secondary | Th17 Level Change | Change in Th17 level in blood to assess improvement of gut mucosal integrity and immunity between baseline and at 12 weeks, measured in cell/μL The results was divided in to unadjusted and adjusted Th17 level change. | The results was divided in to unadjusted and adjusted Th17 level change | Posted | Median | 95% Confidence Interval | cell/μL | 12 weeks |
|
|
|
|
| Secondary | 16S Ribosomal RNA (rRNA) Total | Total of 16SrRNA of translocated gut bacteria in blood, measured in copies/mL, presented as median and interquartile range. | 16S rRNA gene level was measured in all participant before and after intervention. The results were undetected in all participants. | Posted | Median | Inter-Quartile Range | copies/mL | 12 weeks |
|
|
|
| Secondary | Fecal Calprotectin Level Change | Change in calprotectin level in feces to assess gut inflammation between baseline and at 12 weeks, measured in μg/g. The results was divided in to unadjusted and adjusted fecal calprotectin level change | The results are divided in to unadjusted and adjusted fecal calprotectin level change | Posted | Median | 95% Confidence Interval | μg/g | 12 weeks |
|
|
|
|
| Secondary | Amount of Participants With HIV Related Symptoms | A questionnaire called HIV Symptoms Index (Have been validated in Indonesian language) containing self administered 20 questions consisted of 15 somatic and 5 psychological symptoms to assess Human Immunodeficiency Virus (HIV) related symptoms in patients. The total score is calculated by summing the numbers of each symptom (0 = no symptoms, 1 = no disturbing symptoms, 2 = there are symptoms that are a little annoying, 3 = there are disturbing symptoms, 4 = there are very disturbing symptoms), with a minimum score of 0 and maximum 80. Somatic symptoms range from 0-60 and psychological symptoms range from 0-20. An increase in score indicates a worsening condition. Change in HIV Symptoms Index score to assess improvement of somatic and psychological symptoms between baseline and at 12 weeks. The results was divided into somatic and psychological symptoms. Both of them were divided again into unadjusted and adjusted HIV Symptoms Index score Change. | The results was divided into somatic and psychological symptoms. Both of them were divided again into unadjusted and adjusted HIV Symptoms Index score Change. | Posted | Median | Inter-Quartile Range | score on a scale | 0,4,8,12 weeks |
|
|
|
| Other Pre-specified | Change in Food Frequency | Food Frequency Questionnaire (FFQ): A questionnaire consisted of food and drink list and frequency to assess patients' dietary pattern in the past one week. Nutritionist will be asking the participants for the questionnaire questions. The food frequency scaled to "more than one time daily", "once daily", "3-6 times in one week", "1-2 times in one week", "less than one time in one week", "never". We assessed changes in tempeh consumption (as part of FFQ question) after the 12-week intervention by categorizing participants into two groups based on their post-intervention intake: 'seldom' (consuming tempeh 1-2 times per week) and 'often' (consuming tempeh daily). The number of participants in each category was then recorded. | The food frequency is divided in to 2 categories "often and seldom" consume "tempeh" after 12 weeks. | Posted | Number | participants | 0,4, 8, 12 weeks |
|
|
|
|
| 0 |
| 40 |
| 0 |
| 40 |
| 1 |
| 40 |
| EG001 | Placebo | Placebo: Chewing tablet with identical flavour, colour, smell, and size as investigational drug Dosage: 1 chewing tablet Frequency: once daily every night Duration: 12 weeks Placebo: Eligible subjects will be divided into 2 groups randomly (Rillus® or placebo). The colour, smell, flavour, and size of the chewing tablet are the same between active and placebo drugs. Subjects will consume the tablet once daily at night for 12 weeks. | 0 | 40 | 0 | 40 | 3 | 40 |
| Diarrhea | Gastrointestinal disorders | Diarrhea | Non-systematic Assessment |
|
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| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D008722 | Methods |
|
The statistical analysis of adjusted Th17 change after intervention |
| ANCOVA |
| 0.79 |
The threshold for statistical significance was p = 0.05 The variable was adjusted to duration of ARV regimen and baseline CD4 level |
| Mean Difference (Net) |
| 0.1 |
| 2-Sided |
| 95 |
| -0.7 |
| 0.9 |
There is no difference between probiotics - placebo |
| Superiority |
|
The statistical analysis of adjusted Fecal Calprotectin Level change after intervention |
| ANCOVA |
| 0.01 |
The threshold for statistical significance was p = 0.05 The variable was adjusted to duration of ARV regimen and baseline CD4 level |
| Mean Difference (Net) |
| -15.6 |
| 2-Sided |
| 95 |
| -27.6 |
| -3.6 |
Treatment difference = Probiotics - Placebo |
| Superiority |
| The results of unadjusted psychological HIV Symptoms Index score Change |
|
| The results of adjusted psychological HIV Symptoms Index score Change |
|