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Immunologic Response to Kansui in Treated HIV+ Individuals: a Dose Escalation Study

Primary Purpose

HIV, Human Immunodeficiency Virus

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Euphorbia kansui extract powder prepared as tea

About this trial

This is an interventional basic science trial for HIV

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Confirmed HIV-1 infection in adults aged 18 years or older.
Continuous therapy with a DHHS recommended/alternative combination ART for least 36 months (at least 3 agents) at study entry with no regimen changes in the preceding 24 weeks.
Maintenance of undetectable plasma HIV-1 RNA (<40 copies/ml) for at least 36 months. Episodes of single HIV plasma RNA 50-500 copies.ml will not exclude participation if subsequent HIV plasma RNA is <40 copies/ml.
Two CD4+ T cell counts >350 cells/μl in the six months prior to screening.

Exclusion Criteria:

Pre-ART viral load <2000 copies/ml (HIV controllers)
Based on prior history and/or virologic testing, no alternative ART regimens are available in the event that the current ART regimen is compromised as a result of this study.
Recent hospitalization in the last 90 days.
Recent infection in the last 90 days requiring systemic antibiotics.
Recent vaccination within the last 8 weeks prior to study scree or any study blood draw.
Any known history of liver-related diseases including but not limited to: hepatic cirrhosis of decompensated chronic liver diseases; clinically active hepatitis B or C infection as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities; any hepatic impairment, regardless of the graded liver function test abnormalities.
Any known history of gastrointestinal diseases including but not limited to: history of diarrheal illness requiring the use of anti-motility agents including inflammatory bowel disease, chronic diarrhea not otherwise specified; history of gastrointestinal bleeding with hemoglobin below 12.5 g/dL; history of gastric or duodenal ulcers; inflammatory gastrointestinal disease such as Crohn's disease or ulcerative colitis
Any renal disease (eGFR < 90 ml/min) or acute nephritis.
Screening hemoglobin below 12.5 g/dL.
Screening TSH consistent with hypothyroidism.
Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease.
Significant respiratory disease requiring oxygen.
Diabetes or current hypothyroidism.
Participants of reproductive potential or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at screening. All participants of childbearing potential must agree to use a double-barrier method of contraception throughout the study period and up to 90 days after the last dose of kansui.
Exposure to any immunomodulatory drug (including maraviroc) in the16 weeks prior to study.
Prior or current use of experiment agents used with the intent to perturb the HIV-1 viral reservoir.
History of seizures, psychosis, abnormal electroencephalogram or brain damage with significant persisting neurological deficit
Positive test for tuberculosis by either skin test (PPD) or blood interferon-gamma release assay (QuantiFERON).
Significant substance use, which in the opinion of the investigator(s), is likely to interfere with the conduct of the study.

Sites / Locations

University of Utah

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Kansui 1g per day x 1 day

Kansui 1g per day x 2 days

Kansui 1g per day x 3 days

Arm Description

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 1 daily dose.

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 2 consecutive daily doses.

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 3 consecutive daily doses.

Outcomes

Primary Outcome Measures

Safety of Euphorbia kansui extract powder prepared as tea assessed by the number of grade 2 or higher severity adverse events or drug-related laboratory abnormalities that exceed a frequency of 5%

The number of grade 2 or higher severity adverse events (AEs) or drug-related laboratory abnormalities that exceed a frequency of 5% over a 31 day study period.

Secondary Outcome Measures

Early T cell immune activation (%CD69+ CD4+ and CD8+ T cells)

The change in early immune activation levels (as measured by the %CD69+ CD4+ and CD8+ T cells) over a 31 day study period.

T cell immune activation (%CD38+HLA-DR+ CD4+ and CD8+ T cells)

The change in immune activation levels (as measured by the %CD38+HLADR+ CD4+ and CD8+ T cells) over a 31 day study period.

HIV reservoir size (cell-associated HIV RNA)

The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 31 day study period.

HIV reservoir size (plasma HIV RNA)

The change in HIV reservoir size (as measured by ultra-sensitive plasma HIV RNA levels) over a 31 day study period.

Full Information

NCT ID

NCT02531295

First Posted

August 20, 2015

Last Updated

May 8, 2023

Sponsor

University of California, San Francisco

Collaborators

University of Utah, amfAR, The Foundation for AIDS Research

1. Study Identification

Unique Protocol Identification Number

NCT02531295

Brief Title

Immunologic Response to Kansui in Treated HIV+ Individuals: a Dose Escalation Study

Official Title

Immunologic Response to Euphorbia Kansui Extract Powder Prepared as Tea in HIV-infected Antiretroviral Therapy (ART)-Suppressed Individuals: a Dose Escalation Study

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Terminated

Why Stopped

Pause on clinical trial enrollment due to grant funding cuts after COVID-19

Study Start Date

June 1, 2019 (Actual)

Primary Completion Date

March 19, 2020 (Actual)

Study Completion Date

March 19, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, San Francisco

Collaborators

University of Utah, amfAR, The Foundation for AIDS Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine the safety and bioactivity of an herbal supplement called "kansui," which contains several active ingredients such as ingenols that may have a role in helping clear HIV from the body. Kansui has been used in traditional Chinese medicine for centuries to treat various ailments such as for eliminating excess fluid in the abdomen or lungs, loosening phlegm from the chest, and relieving constipation. Based on preliminary in vitro data from our group, kansui extract powder is a potent activator of HIV transpcription in latently infected Jurkat cells. The investigators' hypothesis is that kansui extract powder prepared as tea will be safe and well-tolerated, elicit an in vivo immunologic response, and at the doses administered, increase HIV transcription in latently-infected cells among HIV-infected patients on suppressive antiretroviral therapy.

Detailed Description

Millions HIV-infected individuals are now receiving life-saving antiretroviral therapy (ART). However, mortality remains high, particularly in resource-limited countries. Chronic HIV-infected individuals demonstrate evidence of persistent immune activation despite ART, which is an independent predictor of mortality in this setting. Given the current absence of an effective HIV vaccine, finding a cure for HIV will have a large impact on the long-term health of treated HIV-infected individuals. The key challenge of HIV eradication strategies is the persistence of a small pool of resting memory CD4+ T cells that harbor latent replication-competent HIV, untouched by current ART. One potential strategy to eliminate this reservoir in a "shock and kill" approach in which latency reactivating agents (LRAs) are used to "shock" the virus out of these cells in order for the host immune response, ART, and/or additional immunomodulatory agents to then kill the virus-expressing cells. The goal of the current study is to evaluate the safety and in vivo biological response to an herbal supplement used in traditional Chinese medicine ("kansui)" that has potent in vitro latency reactivating capabilities. Kansui is an inexpensive, readily available herbal supplement prescribed for thousands of years in traditional Chinese medicine and contains active compounds such as ingenols that have been shown to reverse latency in an animal model. A semi-synthetic form of ingenol has been shown to potently reactivate latent simian immunodeficiency virus (SIV) in rhesus macaques and is currently undergoing early drug development. Though kansui has been studied extensively in traditional Chinese medicine, this herbal supplement has never been evaluated for biologic activity in HIV disease using Western scientific research methods. This pilot clinical trial will generate preliminary results regarding the safety and in vivo biologic activity of kansui. Promising results from this study may allow future larger studies which can evaluate the efficacy of this non-pharmacologic agent in the treatment of HIV disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV, Human Immunodeficiency Virus

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Kansui 1g per day x 1 day

Arm Type

Experimental

Arm Description

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 1 daily dose.

Arm Title

Kansui 1g per day x 2 days

Arm Type

Experimental

Arm Description

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 2 consecutive daily doses.

Arm Title

Kansui 1g per day x 3 days

Arm Type

Experimental

Arm Description

Study participants will be given 1 g of Euphorbia kansui extract powder prepared as tea for a total of 3 consecutive daily doses.

Intervention Type

Drug

Intervention Name(s)

Euphorbia kansui extract powder prepared as tea

Other Intervention Name(s)

Kansui

Intervention Description

1 g of Euphorbia kansui extract powder, measured and reconstituted in 4 fluid ounces of boiled water allowed to cool and administered as tea, taken by mouth daily

Primary Outcome Measure Information:

Title

Safety of Euphorbia kansui extract powder prepared as tea assessed by the number of grade 2 or higher severity adverse events or drug-related laboratory abnormalities that exceed a frequency of 5%

Description

The number of grade 2 or higher severity adverse events (AEs) or drug-related laboratory abnormalities that exceed a frequency of 5% over a 31 day study period.

Time Frame

31 days

Secondary Outcome Measure Information:

Title

Early T cell immune activation (%CD69+ CD4+ and CD8+ T cells)

Description

The change in early immune activation levels (as measured by the %CD69+ CD4+ and CD8+ T cells) over a 31 day study period.

Time Frame

31 days

Title

T cell immune activation (%CD38+HLA-DR+ CD4+ and CD8+ T cells)

Description

The change in immune activation levels (as measured by the %CD38+HLADR+ CD4+ and CD8+ T cells) over a 31 day study period.

Time Frame

31 days

Title

HIV reservoir size (cell-associated HIV RNA)

Description

The change in HIV reservoir size (as measured by cell-associated HIV RNA levels) over a 31 day study period.

Time Frame

31 days

Title

HIV reservoir size (plasma HIV RNA)

Description

The change in HIV reservoir size (as measured by ultra-sensitive plasma HIV RNA levels) over a 31 day study period.

Time Frame

31 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Confirmed HIV-1 infection in adults aged 18 years or older. Continuous therapy with a DHHS recommended/alternative combination ART for least 36 months (at least 3 agents) at study entry with no regimen changes in the preceding 24 weeks. Maintenance of undetectable plasma HIV-1 RNA (<40 copies/ml) for at least 36 months. Episodes of single HIV plasma RNA 50-500 copies.ml will not exclude participation if subsequent HIV plasma RNA is <40 copies/ml. Two CD4+ T cell counts >350 cells/μl in the six months prior to screening. Exclusion Criteria: Pre-ART viral load <2000 copies/ml (HIV controllers) Based on prior history and/or virologic testing, no alternative ART regimens are available in the event that the current ART regimen is compromised as a result of this study. Recent hospitalization in the last 90 days. Recent infection in the last 90 days requiring systemic antibiotics. Recent vaccination within the last 8 weeks prior to study scree or any study blood draw. Any known history of liver-related diseases including but not limited to: hepatic cirrhosis of decompensated chronic liver diseases; clinically active hepatitis B or C infection as evidenced by clinical jaundice or Grade 2 or higher liver function test abnormalities; any hepatic impairment, regardless of the graded liver function test abnormalities. Any known history of gastrointestinal diseases including but not limited to: history of diarrheal illness requiring the use of anti-motility agents including inflammatory bowel disease, chronic diarrhea not otherwise specified; history of gastrointestinal bleeding with hemoglobin below 12.5 g/dL; history of gastric or duodenal ulcers; inflammatory gastrointestinal disease such as Crohn's disease or ulcerative colitis Any renal disease (eGFR < 90 ml/min) or acute nephritis. Screening hemoglobin below 12.5 g/dL. Screening TSH consistent with hypothyroidism. Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease. Significant respiratory disease requiring oxygen. Diabetes or current hypothyroidism. Participants of reproductive potential or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at screening. All participants of childbearing potential must agree to use a double-barrier method of contraception throughout the study period and up to 90 days after the last dose of kansui. Exposure to any immunomodulatory drug (including maraviroc) in the16 weeks prior to study. Prior or current use of experiment agents used with the intent to perturb the HIV-1 viral reservoir. History of seizures, psychosis, abnormal electroencephalogram or brain damage with significant persisting neurological deficit Positive test for tuberculosis by either skin test (PPD) or blood interferon-gamma release assay (QuantiFERON). Significant substance use, which in the opinion of the investigator(s), is likely to interfere with the conduct of the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sulggi A Lee, MD PhD

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Adam M Spivak, MD

Organizational Affiliation

University of Utah

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

27977742

Citation

Cary DC, Fujinaga K, Peterlin BM. Euphorbia Kansui Reactivates Latent HIV. PLoS One. 2016 Dec 15;11(12):e0168027. doi: 10.1371/journal.pone.0168027. eCollection 2016.

Results Reference

result

PubMed Identifier

28842560

Citation

Wang P, Lu P, Qu X, Shen Y, Zeng H, Zhu X, Zhu Y, Li X, Wu H, Xu J, Lu H, Ma Z, Zhu H. Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui. Sci Rep. 2017 Aug 25;7(1):9451. doi: 10.1038/s41598-017-07157-0.

Results Reference

result

PubMed Identifier

30031972

Citation

Liu Q, Li W, Huang L, Asada Y, Morris-Natschke SL, Chen CH, Lee KH, Koike K. Identification, structural modification, and dichotomous effects on human immunodeficiency virus type 1 (HIV-1) replication of ingenane esters from Euphorbia kansui. Eur J Med Chem. 2018 Aug 5;156:618-627. doi: 10.1016/j.ejmech.2018.07.020. Epub 2018 Jul 19.

Results Reference

result

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Immunologic Response to Kansui in Treated HIV+ Individuals: a Dose Escalation Study

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