- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01839734
Lubiprostone as a Modulator of Gut Microbial Translocation in HIV With Incomplete CD4 Recovery on Antiretroviral Therapy (LAMBCHOP)
LAMBCHOP-Lubiprostone Activity Among the MicroBiota of the Colon in HIV in Opposing Permeability: Pilot Study of Lubiprostone as a Modulator of Gut Microbial Translocation in HIV With Incomplete CD4 T-cell Recovery on Antiretroviral Therapy
The use of lubiprostone will decrease the levels of immune activation in HIV-infected subjects with incomplete CD4+ T-cell recovery with antiretroviral therapy (ART).
- Lubiprostone will decrease levels of translocated gut microbial products in HIV-infected subjects with incomplete CD4+ T-cell recovery with ART.
- The decrease in levels of translocated gut microbial products will be associated with a decline in the levels of immune activation in HIV-infected subjects with incomplete CD4+ T-cell recovery with ART.
Study Overview
Detailed Description
Incomplete immune recovery in HIV-infected individuals is associated with impaired immune response to antigens, opportunistic infections, cardiovascular disease and malignancies, and increased mortality. Several studies have pointed to increased microbial translocation and immune activation as playing a causative role in these patients with limited CD4 recovery with antiretroviral therapy (ART). The gut mucosa of HIV-infected individuals sustains a rapid and profound depletion of gut mucosal CD4+ T-cells as early as a few days after infection. These changes lead to defects in mucosal immune and epithelial barrier function that allows the translocation of gut microbial products, such as plasma LPS (endotoxin) and bacterial 16s DNA. Plasma endotoxin and bacterial 16s DNA are elevated in HIV-infected individuals and their levels are associated with increased levels of immune activation. ART does not readily reverse the deficits in gut mucosal CD4+ T-cells. The epithelial barrier composed of tight junction complexes of the GI tract is a major defense that must be breached in order for microbial antigens and enterotoxins expressed by pathogenic bacteria to traverse from the lumen of the intestine to the lamina propria of the GI tract. Given recent data demonstrating increased complications and mortality in HIV-infected individuals despite suppressed viral replication on ART, investigators have proposed that adjunctive therapies aimed at reducing microbial translocation and/or its inflammatory consequences could improve the long-term prognosis of HIV-infected individuals. An intervention that decreases the level of translocated gut microbial products using modulators that act at the mucosal tight junction barrier is a strategy that has not been studied in HIV.
LAMBCHOP is a randomized, open-label, controlled two-arm study that will test whether 4 weeks of treatment with lubiprostone, an apical lumen ClC-2 chloride channel activator licensed for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation, reduces levels of translocated gut microbial products and markers of immune activation in HIV-infected subjects on antiretroviral therapy with incomplete CD4 recovery. Lubiprostone is a potent intestinal epithelial secretagogue that has been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine. This study will take advantage of lubiprostone's known effect in vitro to significantly decrease E. coli and S. typhimurium translocation in a concentration-dependent manner and in in vivo mouse studies to promote enhanced protection against translocated pathogenic bacteria by shifting the intestinal microbiota in order to study the role of translocated gut microbial products in driving immune activation in HIV-infected subjects. Blood samples and stool specimens will be collected at several time points during the study to measure markers of cellular activation, inflammation, gut translocation, and coagulation. Safety assessments will be performed at screening, entry, and several post-entry visits. The primary objectives of the study is to determine whether there is a significant difference in levels of immune activation and gut microbiome after 4 weeks of study drug in those who received lubiprostone.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Illinois
-
Chicago, Illinois, United States, 60612
- Ruth M. Rothstein CORE Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
- On tenofovir/emtricitabine/efavirenz single tablet combination therapy for at least 72 weeks prior to study entry.
- No plans to change the antiretroviral regimen at least in the next 3 months after study entry.
- CD4+ cell count < 350 cells/mm3 obtained within 120 days prior to study entry at any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
- All previous CD4+ cell counts should be < 350 cells/mm3 for at least 72 weeks prior to study entry while subjects were on ART.
- Documentation of HIV-1 RNA below the limit of detection (e.g., < 50 copies/mL on Roche Amplicor HIV-1 Monitor assay, < 75 copies/mL on the Versant HIV-1 RNA assay by branched DNA, < 400 copies/mL on a standard Roche Amplicor assay, < 40 copies/mL on the Abbott m2000sp/m2000rt real-time PCR test, < 48 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1 assay) verified by at least two measurements prior to study entry, one of which must be at least 48 weeks prior to study entry and one measurement that was obtained between 121 days and 48 weeks prior to study entry.
- Screening HIV-1 RNA below the limit of detection obtained within 120 days prior to study entry using a FDA -approved assay (e.g., < 50 copies/mL on Roche Amplicor HIV-1 Monitor assay, < 75 copies/mL on the Versant HIV-1 RNA assay by branched DNA, < 40 copies/mL on the Abbott m2000sp/m2000rt real-time PCR test, < 48 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1 assay).
Fasting laboratory values obtained within 45 days prior to entry as follows:
- Absolute neutrophil count (ANC) ≥ 1000/mm3
- Hemoglobin ≥ 10.0 g/dL
- Platelet count ≥ 50,000/mm3
- International normalized ratio (INR)
- Female subjects of reproductive potential (defined as girls who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months; i.e., those who have had menses within the preceding 24 months or have not undergone a sterilization procedure [hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral salpingectomy]) must have a negative serum or urine β-HCG pregnancy test with a sensitivity of at least 50 mIU/mL performed within 24 hours prior to study entry.
If participating in sexual activity that could lead to pregnancy, the female subject must agree to use one form of contraceptive as listed below while receiving protocol-specified treatment and for 4 weeks after stopping the treatment.
- If the female subject is not of reproductive potential (girls who have not reached menarche, women who have been post-menopausal for at least 24 consecutive months, or women who have undergone surgical sterilization, e.g., hysterectomy, bilateral oophorectomy, or bilateral tubal ligation or salpingectomy), she is eligible without requiring the use of a contraceptive. Self report is acceptable documentation of sterilization, other contraceptive methods, and menopause.
- Men and women age ≥ 18 and ≤ 65 years of age.
- Ability and willingness of subject or legally authorized representative to provide informed consent.
Exclusion Criteria:
- Active diarrhea (3 or more unformed stools per day) within 28 days prior to study entry (except if site investigator or primary care provider attributes diarrhea to antiretroviral or azithromycin use).
- History of or active inflammatory bowel disease.
- History of significant liver disease, defined as having chronic liver disease (including chronic alcoholic liver disease, hepatitis B or C), plus either: a) ascites, b) encephalopathy, or c) a Child-Pugh Score of > 7.
- Receipt of antimicrobial therapy within 30 days prior to study entry.
NOTE: Antimicrobial use for prophylaxis of opportunistic infections, e.g., azithromycin or trimethoprim-sulfamethoxazole, is allowed.
- Active infection requiring the use of antibiotics within 30 days prior to study entry.
- Known allergy/sensitivity or any hypersensitivity to components of study drug or their formulation.
- Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to entry.
Use of any of the following medications for more than 3 consecutive days within the 60 days prior to study entry:
- Immunosuppressives (e.g., azathioprine, corticosteroids [physiologic replacement doses are allowed], cyclosporine, mycophenolate, NSAIDs (nonsteroidal anti-inflammatory drugs), sirolimus, sulfasalazine, tacrolimus)
- Immune modulators (e.g., cytokines [e.g., IL-2], granulocyte colony stimulating factor, growth hormone, tumor necrosis factor antagonists, thalidomide)
- Antineoplastic agents
- Probiotics (defined as products that contain significant amounts of live microorganisms and are ingested for specific health benefits, e.g., yogurt with live and active cultures, Lactobacillus GG, Saccharomyces boulardii)
- Anticoagulants (e.g., warfarin and heparin)
- Vaccinations within 1 week prior to the pre-entry or study entry visits.
NOTE: Subjects are encouraged to get the flu vaccine prior to study pre-entry visit.
- Participation on any HIV immunotherapy/therapeutic vaccination trials within 6 months prior to study entry.
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- Breastfeeding.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: No intervention
|
|
Experimental: Lubiprostone
4 weeks of treatment with lubiprostone 24 mcg by mouth (PO) once-daily (Interventional Group)
|
Lubiprostone 24 mcg by mouth (PO) once-daily
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in Gut Microbial Translocation (iFABP)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median iFABP MT marker change at week 4 from baseline aggregate median values
|
Baseline and 4 weeks
|
Changes in Gut Microbial Translocation (Zonulin)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median Zonulin MT marker change at week 4 from baseline aggregate median values.
|
Baseline and 4 weeks
|
Changes in Gut Microbial Translocation (sCD14)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median sCD14 MT marker change at week 4 from baseline aggregate median values
|
Baseline and 4 weeks
|
Changes in Gut Microbial Translocation (sCD163)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median sCD163 MT marker change at week 4 from baseline aggregate median values
|
Baseline and 4 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in Systemic Inflammation (IL-6)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median IL-6 inflammation marker change at week 4 from baseline aggregate median values.
|
Baseline and 4 weeks
|
Changes in Systemic Inflammation (hsCRP)
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median hsCRP inflammation marker change at week 4 from baseline aggregate median values
|
Baseline and 4 weeks
|
Changes in Peripheral CD4+
Time Frame: Baseline and 4 weeks
|
Summary difference of participant's median CD4+ change at week 4 from baseline aggregate median values
|
Baseline and 4 weeks
|
Number of Participants With Adverse Events During Study Period
Time Frame: 4 weeks
|
Safety monitoring, defined as Grade ≥ 2 signs and symptoms, Grade ≥ 2 laboratory abnormalities, and other serious adverse events (SAEs) not otherwise specified.
|
4 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Gregory Huhn, MD, MPHTM, Ruth M. Rothstein CORE Center
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 13-071
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on HIV
-
University of Alabama at BirminghamMobile County Health Deparment; Alabama Department of Public HealthRecruitingHIV | HIV Testing | HIV Linkage to Care | HIV TreatmentUnited States
-
ANRS, Emerging Infectious DiseasesHopital Universitaire Robert-Debre; Institut de Recherche pour le Developpement and other collaboratorsUnknownHIV | HIV-uninfected Children | Children Exposed to HIVCameroon
-
French National Agency for Research on AIDS and...Elizabeth Glaser Pediatric AIDS FoundationCompletedPartner HIV Testing | Couple HIV Counseling | Couple Communication | HIV IncidenceCameroon, Dominican Republic, Georgia, India
-
University of MinnesotaWithdrawnHIV Infections | HIV/AIDS | Hiv | AIDS | Aids/Hiv Problem | AIDS and InfectionsUnited States
-
CDC FoundationGilead SciencesUnknownHIV Preexposure Prophylaxis | HIV ChemoprophylaxisUnited States
-
Africa Health Research InstituteLondon School of Hygiene and Tropical Medicine; University College, London; University... and other collaboratorsRecruiting
-
Massachusetts General HospitalNational Institute of Mental Health (NIMH); Fenway Community Health; Tuberculosis...CompletedHIV/STI Risk | HIV/STI IncidenceUnited States, India
-
Hospital Clinic of BarcelonaCompletedIntegrase Inhibitors, HIV; HIV PROTEASE INHIBSpain
-
Erasmus Medical CenterNot yet recruitingHIV Infections | Hiv | HIV-1-infection | HIV I InfectionNetherlands
-
University of WashingtonNational Institute of Mental Health (NIMH)RecruitingHIV Prevention | HIV Preexposure Prophylaxis | ImplementationKenya
Clinical Trials on Lubiprostone
-
Sucampo Pharma Americas, LLCTakedaCompletedHealthy VolunteersUnited States
-
Baylor College of MedicineUniversity of South FloridaCompletedParkinson's DiseaseUnited States
-
Texas Tech University Health Sciences Center, El...Completed
-
Dartmouth-Hitchcock Medical CenterTakeda Pharmaceuticals North America, Inc.CompletedChronic Idiopathic ConstipationUnited States
-
University of ArkansasTakeda Pharmaceuticals North America, Inc.CompletedConstipation | Cystic FibrosisUnited States
-
Helwan UniversityCompleted
-
University of South AlabamaTakeda; Sucampo Pharmaceuticals, Inc.TerminatedConstipationUnited States
-
Brooke Army Medical CenterTakedaCompletedBowel Preparation for ColonoscopyUnited States
-
Henry Ford Health SystemTakeda Pharmaceuticals North America, Inc.CompletedColonoscopyUnited States
-
Mayo ClinicNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); T... and other collaboratorsCompleted