HIV/AIDS-associated Fatigue Clinical Trial
Official title:
American Ginseng to Improve HIV-Associated Fatigue: A Randomized, Placebo-Controlled, Multiple-Dose Escalation Clinical Trial
The purpose of this study is to determine whether American ginseng is effective in the treatment of HIV-associated fatigue.
STUDY DESIGN Chronic fatigue is a major problem for HIV-infected patients and contributes to
decreased quality of life and physical functioning, higher levels of psychological distress,
and antiretroviral non-adherence. The etiology of fatigue in HIV-infected patients is
unknown, but changes in systemic inflammation may play a contributing role. The mechanism of
action of ginseng in the treatment of fatigue is also not clear, but in its role as a
purported "adaptogen," it may decrease fatigue by altering systemic inflammation. Ginseng is
one of the most popular botanical products in the US and is marketed to improve fatigue and
vitality. Our preliminary data suggested that American ginseng at 1000-2000 mg/day may
decrease fatigue in cancer patients. HIV-infected patients frequently use ginseng, in part
because they perceive these therapies to be safer than more conventional therapies.
We hypothesized that a standardized American ginseng formulation will improved HIV-related
fatigue. To test this hypothesis we propose a 6-week double-blind, placebo-controlled trial,
parallel study of four weeks of treatment involving two doses of American ginseng or placebo
(1000mg/day or 3000 mg/day) in 120 HIV-infected patients with clinically significant fatigue,
as defined by their scores on the Fatigue Severity Scale. Patients will be treated with
American ginseng or placebo every morning for a total of two doses of 1000 mg/day or 3000
mg/day. A smaller cohort of 12 out of 120 subjects will be enrolled initially to monitor
closely for confirmed virologic failure, If confirmed virologic failure is not observed,
enrollment will continue to the proposed 120 subjects. Virologic failure is defined as two
consecutive plasma viral loads >200 cells according to the 2012 Department of Health Humans
Services Guidelines for the use of antiretroviral agents in HIV-1 infected adults and
adolescents
The proposed doses of American ginseng are the same as those used in our previous trials.
American ginseng 1000 mg/day showed efficacy in ameliorating fatigue in cancer patients. The
highest dose of American ginseng (3000 mg/day) selected for this study was derived from our
previous American ginseng trial.
Change on scores of the Fatigue Severity Scale (FSS) between American ginseng and placebo
groups at baseline, and treatment weeks 2, 4, and 6 (the last safety visit two weeks after
completing the 4-week treatment period with American ginseng or placebo) will be calculated.
The primary comparison of interest will involve the primary endpoint of the average change in
the FSS scale score from baseline to the end of treatment. Other instruments to supplement
the FSS and further assess fatigue will be a modified version of the Brief Fatigue Inventory
(BFI), The Epworth Sleepiness Scale (ESS), the Patient Health Questionnaire (PHQ-9), Insomnia
Severity Index (ISI), the Medical Outcomes Study HIV Health Survey (MOS-HIV), the Clinical
Global Impressions (CGI) of Change Scale, and Patient-Reported Outcomes Measurement
Information System (PROMIS) fatigue. To further elucidate the mechanism of HIV-related
fatigue, we will evaluate the effects of American ginseng and placebo on markers of systemic
inflammation such as IL-6 and soluble receptors of tumor necrosis factor (TNF) α 1 and 2
(sTNFR1 and sTNFR2), at baseline and weeks 2, 4, and 6. cluster of differentiation 4 (CD4)
cell counts, plasma HIV RNA levels, and adverse events (AEs) will also be assessed for safety
purposes.
DURATION:
The total duration of this study is 6 weeks. Participants will receive American ginseng or
placebo during the first 4 weeks of the study. On week 6 participants will complete their
final post treatment safety study visit.
POPULATION AND SAMPLE SIZE:
120 HIV-infected subjects (40 in the American ginseng 1000 mg/day arm, 40 in the American
ginseng 3000 mg/day arm, 20 in the placebo 1000 mg/day arm, and 20 in the placebo 3000 mg/day
arm).
REGIMEN:
This is a randomized, placebo-controlled, longitudinal, parallel study with two doses of
American ginseng. As shown in the study schematic figure, two doses of American ginseng or
placebo (1000 or 3000 mg/day) will be given to 120 HIV-infected patients (40 in the American
ginseng 1000 mg/day arm, 40 in the American ginseng 3000 mg/day arm, 20 in the placebo 1000
mg/day arm, and 20 in the placebo 3000 mg/day arm) with clinically significant fatigue.
Participants will receive American ginseng or placebo for a total of 4 weeks and will be
followed for a total of 6 weeks (week 6 is the last safety visit 2 weeks after completing the
4-week treatment period with American ginseng or placebo).
American ginseng will be continued for Grades 1 and 2 toxicities at the discretion of the
investigator. Treatment will be discontinued for subjects experiencing any grade ≥3 study
drug toxicity. Evaluations for the early termination visit will be completed for these
subjects. Participants who discontinue treatment secondary to toxicity will be followed until
resolution, return to baseline values, or an adequate explanation can be given for their
condition. Subjects requiring dose modifications/reductions/interruptions of American
ginseng/placebo to manage toxicities will be followed off study drugs. The total number of
patients accrued hence will be 120 patients (40 in the American ginseng 1000 mg/day arm, 40
in the American ginseng 3000 mg/day arm, 20 in the placebo 1000 mg/day arm, and 20 in the
placebo American ginseng 3000 mg/day arm).
STUDY DURATION The total duration of this study is six weeks. Participants will receive
American ginseng or placebo during the first 4 weeks of the study. On week 6 participants
will complete their final post treatment safety study visit.
STUDY AGENT/INTERVENTION DESCRIPTION Two doses of American ginseng or placebo (1000 mg/day or
3000 mg/day) every morning by mouth for a 4-week period.
PRIMARY AND SECONDARY OBJECTIVES The overall objective of this study is to determine the
effect of American ginseng on fatigue in HIV-infected subjects. HIV-infected subjects with
fatigue will be randomized to receive two doses (1000 mg/day or 3000 mg/day) of standardized
American ginseng or placebo, and their levels of fatigue and quality of life will be
assessed. We will also quantify proinflammatory cytokines in the placebo and American
ginseng-treated groups to further elucidate the mechanism of HIV-related fatigue, and the
effects of American ginseng on these markers.
ENDPOINTS
Primary Endpoint: Change in FSS total score from baseline to end of four weeks of treatment.
Secondary Endpoints: Change from baseline and values observed at 2, 4, and 6 weeks
post-baseline for the following measures: BFI-global assessment score ESS score PHQ-9 total
score ISI score MOS-HIV scale total score, Gene Importance Calculator (GIC) score PROMIS
fatigue scale score Serum cytokines (IL-6, sTNFR1, sTNFR2) CD4 cell counts, proportion with
detectable plasma HIV RNA, AEs will be measured using the Division of AIDS Table for Grading
the Severity of Adults Adverse events.
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