End-Stage Renal Disease, Gut Microbiome Dysbiosis
Conditions
Keywords
hemodialysis, p-inulin, gut microbiome
Brief summary
The Microbiome trial is a non-randomized, open-label, sequential, multi-center study of p-inulin for patients with hemodialysis-dependent end-stage renal disease.
Detailed description
This primary objective of this exploratory study is to characterize the safety and tolerability of p-inulin (Prebiotin®, provided by JGI Medical) in altering the composition and function of the human gut microbiome, thereby reducing the generation of gut-derived uremic toxins, improving gut barrier function and attenuating systemic inflammation in patients treated with maintenance hemodialysis. The study also aims to assess the feasibility of conducting a full-scale trial of p-inulin. The primary efficacy parameters of the trial will be intra- and inter-participant variability in gut metabolites and bacterial composition. Secondary parameters of interest include tolerability and safety of p-inulin, willingness of hemodialysis patients to enroll in a study requiring repeated collection of stool samples, and participant adherence to agent treatment and specimen collection schedules.
Interventions
DIETARY_SUPPLEMENTp-inulin
12 week self-administered treatment phase
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Brigham and Women's Hospital
George Washington University
Vanderbilt University
University of Washington
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
This is a sequential trial that included three sequential phases: 1. Pre-treatment phase: 8 weeks during which no treatment was administered 2. p-Inulin phase: 12 weeks during which p-inulin was administered 8g orally twice daily 3. Post-treatment phase: 8 weeks during which no treatment was administered. Eleven of the 13 participants in the p-inulin phase entered the post-treatment phase. The other two withdrew prior to the post-treatment phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Maintenance hemodialysis therapy for end-stage renal disease * At least 18 years of age * At least 90 days since hemodialysis initiation * Self-reported average stool frequency of at least 1 every other day * For women of childbearing potential, willingness to use a highly effective method of birth control for up to 4 weeks after the last dose of p-inulin. * Ability to provide consent
Exclusion criteria
* Use of prebiotics or probiotics during the past 8 weeks * Consumption of probiotic yogurt during the past 2 weeks * Use of antibiotics within the past 8 weeks * Presence of HIV infection, chronic wound infection, osteomyelitis, or current hemodialysis * Inflammatory bowel disease, chronic diarrhea, current C. difficile infection * Cirrhosis or chronic active hepatitis * Anticipated kidney transplantation, change to peritoneal dialysis, or transfer to another dialysis unit within 9 months * Expected survival less than 9 months * Pregnancy, anticipated pregnancy, or breastfeeding * Incarceration * Participation in another intervention study * Severe anemia defined as hemoglobin \<9.0 g/dl within the past 4 weeks as documented in the dialysis unit patient record
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Within Participant Variability in Microbiome Composition by Treatment Phase | 28 weeks | The weighted UniFrac distance was used to compute the distances for each sample. Weighted UniFrac distance uses species abundance information and weights the branch length with abundance difference. Weighted UniFrac distance is most sensitive to detect change in abundant lineages since it uses absolute abundance difference in its definition. |
| Within Participant Variability in Stool Metabolome by Treatment Phase | 28 weeks | The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms. |
| Within Participant Variability in Plasma Metabolome by Treatment Phase | 28 weeks (8 weeks pre-treatment, 12 weeks of treatment, 8 weeks post-treatment) | The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (Safety Outcome) | 28 weeks | -Adverse events per participant related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System |
| Number of Serious Adverse Events (Safety Outcome) | 28 weeks | Serious adverse events categorized by body systems, related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System |
| Rate of Enrollment Refusal (Feasibility Outcome) | 1 year | Enrollment refusal rate |
| Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | GSRS was assessed at Weeks 0, 4, 8, 12, 16, 20, 24 and 28. | Gastrointestinal symptoms as measure by the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS total score is the sum of 15 0-3 items where 0 indicates absence and 3 an extreme degree of the symptom. A higher score indicates worse outcome. The minimum score is 0, the maximum score is 45. |
| Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 28 weeks | Proportion of completed blood sample collections |
| Adherence Rate of P-inulin Use (Feasibility Outcome) | 12 weeks | Proportion of p-inulin packets used |
| Rate of Study Withdrawal (Feasibility Outcome) | 28 weeks | Number of withdrawals during each phase of the study |
| Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 28 weeks | Percent of expected completed protocol-specified stool sample collections |
| Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome) | 12 weeks | -Early discontinuation of p-inulin |
| Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome) | 12 weeks | -Reduction in p-inulin dose |
Countries
United States
Participant flow
Recruitment details
The protocol allowed for enrollment of up to 20 individuals with the goal or having 10 participants complete the first 20 weeks of the study with satisfactory completeness of biosample collection.
Participants by arm
| Arm | Count |
|---|---|
| All Participants This is a sequential study in which participants are observed (no intervention) for 8 weeks (pre-treatment), then participants self-administer p-inulin 8g orally twice daily for 12 weeks (treatment phase), and then observed for a final 8 weeks during which no treatment was administered (post-treatment). | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant received kidney transplant | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 48.2 years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 1 / 13 | 2 / 11 | 0 / 11 |
| serious Total, serious adverse events | 2 / 13 | 0 / 11 | 1 / 11 |
Outcome results
Primary
Within Participant Variability in Microbiome Composition by Treatment Phase
The weighted UniFrac distance was used to compute the distances for each sample. Weighted UniFrac distance uses species abundance information and weights the branch length with abundance difference. Weighted UniFrac distance is most sensitive to detect change in abundant lineages since it uses absolute abundance difference in its definition.
Time frame: 28 weeks
Population: Two participants withdrew at the beginning of the second phase of the trial. One participant with antibiotic use was not included in the microbiome composition analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Study Cohort | Within Participant Variability in Microbiome Composition by Treatment Phase | treatment | 0.175 weighted unifrac distrance |
| Full Study Cohort | Within Participant Variability in Microbiome Composition by Treatment Phase | post-treatment | 0.210 weighted unifrac distrance |
| Full Study Cohort | Within Participant Variability in Microbiome Composition by Treatment Phase | pre-treatment | 0.165 weighted unifrac distrance |
Primary
Within Participant Variability in Plasma Metabolome by Treatment Phase
The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms.
Time frame: 28 weeks (8 weeks pre-treatment, 12 weeks of treatment, 8 weeks post-treatment)
Population: Two participants withdrew at the beginning of the second phase of the trial. One participant with antibiotic use was not included in the microbiome composition analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Study Cohort | Within Participant Variability in Plasma Metabolome by Treatment Phase | pre-treatment | 9.48 Euclidean distance |
| Full Study Cohort | Within Participant Variability in Plasma Metabolome by Treatment Phase | treatment | 9.47 Euclidean distance |
| Full Study Cohort | Within Participant Variability in Plasma Metabolome by Treatment Phase | post-treatment | 9.72 Euclidean distance |
Primary
Within Participant Variability in Stool Metabolome by Treatment Phase
The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms.
Time frame: 28 weeks
Population: Two participants withdrew at the beginning of the second phase of the trial. One participant with antibiotic use was not included in the microbiome composition analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Study Cohort | Within Participant Variability in Stool Metabolome by Treatment Phase | pre-treatment | 14.49 Euclidean distance |
| Full Study Cohort | Within Participant Variability in Stool Metabolome by Treatment Phase | treatment | 15.70 Euclidean distance |
| Full Study Cohort | Within Participant Variability in Stool Metabolome by Treatment Phase | post-treatment | 16.77 Euclidean distance |
Secondary
Adherence Rate of P-inulin Use (Feasibility Outcome)
Proportion of p-inulin packets used
Time frame: 12 weeks
Population: This is a sequential trial. The 13 participants from the pre-treatment phase moved to the p-inulin phase. Eleven of the 13 participants entered the post-treatment phase. Two participants withdrew prior to the post-treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Study Cohort | Adherence Rate of P-inulin Use (Feasibility Outcome) | 0 percent |
| Week 4 | Adherence Rate of P-inulin Use (Feasibility Outcome) | 89.5 percent |
| Week 8 | Adherence Rate of P-inulin Use (Feasibility Outcome) | 0 percent |
Secondary
Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome)
Proportion of completed blood sample collections
Time frame: 28 weeks
Population: This is a sequential trial. The 13 participants from the pre-treatment phase moved to the p-inulin phase. Eleven of the 13 participants entered the post-treatment phase. Two participants withdrew prior to the post-treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Study Cohort | Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 99 percentage of expected |
| Week 4 | Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 100 percentage of expected |
| Week 8 | Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 94 percentage of expected |
Secondary
Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome)
Gastrointestinal symptoms as measure by the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS total score is the sum of 15 0-3 items where 0 indicates absence and 3 an extreme degree of the symptom. A higher score indicates worse outcome. The minimum score is 0, the maximum score is 45.
Time frame: GSRS was assessed at Weeks 0, 4, 8, 12, 16, 20, 24 and 28.
Population: Two participants withdrew at the beginning of the second phase of the trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Full Study Cohort | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 5.69 score on a scale | Standard Deviation 3.35 |
| Week 4 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 6.23 score on a scale | Standard Deviation 3.65 |
| Week 8 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 3.68 score on a scale | Standard Deviation 5.36 |
| Week 12 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 4.36 score on a scale | Standard Deviation 3.75 |
| Week 16 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 6.00 score on a scale | Standard Deviation 6.47 |
| Week 20 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 5.27 score on a scale | Standard Deviation 5.37 |
| Week 24 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 3.45 score on a scale | Standard Deviation 2.77 |
| Week 28 | Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | 3.91 score on a scale | Standard Deviation 2.59 |
Secondary
Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome)
-Early discontinuation of p-inulin
Time frame: 12 weeks
Population: This outcome is only relevant during the p-inulin phase.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Full Study Cohort | Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome) | 0 Participants |
| Week 4 | Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome) | 0 Participants |
| Week 8 | Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome) | 0 Participants |
Secondary
Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome)
-Reduction in p-inulin dose
Time frame: 12 weeks
Population: Three participants reduced their p-inulin dose. This analysis only applies to the 12 week treatment arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Full Study Cohort | Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome) | 0 Participants |
| Week 4 | Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome) | 3 Participants |
| Week 8 | Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome) | 0 Participants |
Secondary
Number of Participants With Adverse Events (Safety Outcome)
-Adverse events per participant related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System
Time frame: 28 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Study Cohort | Number of Participants With Adverse Events (Safety Outcome) | 1 participants |
| Week 4 | Number of Participants With Adverse Events (Safety Outcome) | 2 participants |
| Week 8 | Number of Participants With Adverse Events (Safety Outcome) | 0 participants |
Secondary
Number of Serious Adverse Events (Safety Outcome)
Serious adverse events categorized by body systems, related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System
Time frame: 28 weeks
Population: This is a sequential trial. The 13 participants from the pre-treatment phase moved to the p-inulin phase. Eleven of the 13 participants entered the post-treatment phase. Two participants withdrew prior to the post-treatment phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Study Cohort | Number of Serious Adverse Events (Safety Outcome) | 3 Serious Adverse Events |
| Week 4 | Number of Serious Adverse Events (Safety Outcome) | 0 Serious Adverse Events |
| Week 8 | Number of Serious Adverse Events (Safety Outcome) | 1 Serious Adverse Events |
Secondary
Rate of Enrollment Refusal (Feasibility Outcome)
Enrollment refusal rate
Time frame: 1 year
Population: Data not collected
Secondary
Rate of Study Withdrawal (Feasibility Outcome)
Number of withdrawals during each phase of the study
Time frame: 28 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Full Study Cohort | Rate of Study Withdrawal (Feasibility Outcome) | 0 Participants |
| Week 4 | Rate of Study Withdrawal (Feasibility Outcome) | 2 Participants |
| Week 8 | Rate of Study Withdrawal (Feasibility Outcome) | 0 Participants |
Secondary
Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome)
Percent of expected completed protocol-specified stool sample collections
Time frame: 28 weeks
Population: This is a sequential trial. The 13 participants from the pre-treatment phase moved to the p-inulin phase. Eleven of the 13 participants entered the post-treatment phase. Two participants withdrew prior to the post-treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Study Cohort | Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 97 percentage of expected |
| Week 4 | Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 100 percentage of expected |
| Week 8 | Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | 97 percentage of expected |