COVID-19, Diarrhea
Conditions
Brief summary
The Center for Disease Control (CDC) and World Health Organization (WHO) have deemed the COVID-19 virus a global pandemic of unprecedented severity in modern times. In 2019, this novel Coronavirus (COVID-19) emerged from the Asian continent and has now caused upwards of 1million deaths and over 6 million infections globally. Currently, the estimated global economic impact is over 5 Trillion dollars. Understanding the host response to pathogens, specifically the cellular and humoral responses, has played an important role in new non-antibiotic therapies. Bismuth subsalicylate (Pepto-Bismol) has a potential role in the clearance and/or recurrence of enteric viral infections.
Detailed description
Readily available over-the-counter (OTC) medication for symptomatic relief and appropriate oral hydration can be health saving measures of great convenience for those affected by enteric bacterial and viral infections. BSS is a non-proprietary monograph product that is available in the USA and abroad, over-the-counter (OTC). Of all OTC medications for traveller's diarrhea (TD), bismuth subsalicylate (BSS) has the greatest antimicrobial activity against pathogenic bacteria .BSS has also exhibited significant inhibition on viral invasion of host cells and viral efficacy. Both BSS and bismuth oxychloride (BiOCl, which is formed in the stomach after ingestion of BSS) at low concentration (0.004-0.13mg/mL) significantly reduced norovirus (NoV) RNA levels, suggesting an in vivo antiviral mechanism. BSS has also been shown to have antiviral activity since it inhibited replication of 4 strains of rotavirus in tissue culture cells and caused a dose-dependent reduction in the growth of several enteric viruses. Historically, BSS has been indicated and effectively used for the treatment of TD or enteric infection, mainly when vomiting occurs. Although the safety and efficacy of BSS is well known, some of the research done with BSS resides within the industry and have not been published. We have recently completed an extensive meta-analysis using unpublished clinical studies regarding BSS safety and efficacy. Meta-analyses of randomized controlled clinical trials were performed with studies specifically designed to capture prevention of manifestation and relief of diarrhea.
Interventions
DRUGBismuth Subsalicylate 262 milligram (mg) Oral Tablet, Chewable
Pepto bismol (bismuth subsalicylate)
OTHERPlacebo oral tablet without BSS
Placebo Tablet made by P & G to contain everything except active ingredient ( BSS)
Sponsors
Procter and Gamble
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Member of research team not involved in patient care.
Intervention model description
Open label trial of Bismuth subsalicylate (10 patients) followed by a second, placebo controlled study (50 patients) for mild to moderate COVID-19+ patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
To be eligible to participate in the study, patients must meet the following criteria: Ability to provide written or remote informed consent (telephone and DocuSign) Ability to comply with study requirements, Men or women 18 to 85 years of age, inclusive Current diagnosis of an initial occurrence of non-severe, non-complicated COV+ infection as defined by: * Presence COVID-19 in the saliva using point of care (POC) Qualitative real time - polymerase chain reaction (QRT- PCR) assay. * Management in an outpatient (i.e., non-hospital) or inpatient setting NOT on a ventilator. * Alert and awake * Able to chew the study drug completely. * Women should fulfill one of the following criteria: * Answer in the affirmative that they are not or could not be pregnant * Post-menopausal; either amenorrhea ≥12 months or follicle stimulating hormone \>20 mIU/mL (milli-International units) * Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation. * Women of childbearing potential participating in heterosexual sexual relations must be willing to use adequate contraception from Screening through the 21 Day visit, per Section 10.2. Standard of care COVID-19 treatment is acceptable.
Exclusion criteria
Patients with any of the following will be excluded from admission into the study: * Existence of an intra-abdominal abscess, enteric fistula, or symptomatic bowel obstruction * History of allergy to salicylates. * History of short gut syndrome, active ulcer or recent history of GI bleeding or melena. * Systemic chemotherapy for the treatment of cancer during the 60 days prior to consent or planned during the study * Active use of remdesivir. * vaccination for COVID within 30 days. * Current use of drugs that control diarrhea or affect peristalsis (e.g., loperamide. Opiates can be used in hospitalized patients and with outpatients if they are prescribed to a patient), or any anticipated use during the study * Active drug, chemical, or alcohol dependency as determined by Investigator through history or urine toxicology screen * Enrollment in any other investigational drug or device study known to interfere with Pepto bismol (bismuth subsalicylate) within the GI tract, within 30 days prior to Randomization (Day 1) or within 5 half-lives of the last dose of the previous investigational compound, whichever is longer. Vaccines are not exclusionary as they do not interfere with the mechanism of the study drug. * Severe acute illness unrelated to COVID-19 * Pregnant, breast-feeding, or considering becoming pregnant during the study * Planned hospitalization or surgery during the study * Any medical, psychiatric, social, or other circumstances that may interfere with study compliance, completion, or accurate assessment of study outcomes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measure of Daily Stool Frequency for Patients With COVID Treated With Bismuth | 3 days | Number of bowel movements recorded over the 3 day study. Baseline (BL) /day1 + Day 2 + Day 3 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP) | Day 3 - or 48 hours after starting BSS | Salivary SARS-CoV2 measured daily. The final outcome is SARS-CoV2 status on day 3. Clearance of SARS-CoV2 ( a negative salivary SARS-CoV2 RT-LAMP test). or Remained SARS-CoV2+ ( a positive salivary SARS-CoV2. RT-LAMP test) |
Countries
United States
Participant flow
Recruitment details
The open label feasibility arm started Oct 2020 and completed Feb 2021 at University of Louisville Hospitals. First patient consented and received drug was on Oct 27 2020, last patient Feb 20 2021. This was pre vaccine environment. Public availability of vaccine in Kentucky was March of 2021. 19 patients received drug with only 10 patients completing therapy. Placebo controlled study (50 patients) was cancelled. If started a new study will be entered in Clinical.Trials.gov
Pre-assignment details
19 patients received drug. 9 patients received some Bismuth Subsalicylate (BSS), 10 patients completed 3 days of BSS therapy. All was done in pre-vaccine environment. 25 patients consented received no drug.
Participants by arm
| Arm | Count |
|---|---|
| Open Label BSS Therapy -Completed All patients will be assigned to the treatment group for the first 10 patients treated with open label BSS.
open label BSS (pepto Bismol): Pepto bismol (bismuth subsalicylate)
10 who completed 3 day therapy and provided all samples | 10 |
| Open Label BSS Therapy - Those Who DID NOT Complete 9 patients who got some BSS - but did not complete 3 day therapy | 9 |
| Open Label - BSS Therapy No BSS Given Those 25 patients who consented but received no BSS therapy. | 25 |
| Cancelled Placebo-control & BSS Arm The Subsequent 50 patients would have been randomized to either placebo or BSS. The patients will be assigned by envelope containing a symbol for either active drug or placebo (or other suitable randomization event) by a member of the research team not directly involved in the clinical trial.
We could not recruit due to confiscation and expiration of placebo.
open label BSS (pepto Bismol): Pepto bismol (bismuth subsalicylate) | 0 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 0 |
| Overall Study | Early on Nurse/Physician communication issue | 0 | 3 | 0 |
| Overall Study | Inconclusive saliva SARS CoV2 test (3X) | 1 | 0 | 0 |
| Overall Study | lack of transportation not wanting to return | 4 | 8 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Medications. Standard of Care medications were changing rapidly Protocol needed constant amending | 0 | 4 | 0 |
| Overall Study | Negative primary or secondary salivary SARS-CoV2 test | 0 | 6 | 0 |
| Overall Study | Transferred to ICU for non-COVID-19 related problem | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Open Label BSS Therapy -Completed | Open Label BSS Therapy - Those Who DID NOT Complete | Open Label - BSS Therapy No BSS Given | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 10 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 15 Participants | 26 Participants |
| Age, Continuous | 52.70 year STANDARD_DEVIATION 21.79 | 65.22 year STANDARD_DEVIATION 8.84 | 60.6 year STANDARD_DEVIATION 14.58 | 59.75 year STANDARD_DEVIATION 15.84 |
| Baseline/Day1 3 symptom score | 2.4 Scores on scale | 2.1 Scores on scale | — | 2.4 Scores on scale |
| Baseline/Day1 5 symptom score | 3.8 Scores on a Scale | 3.2 Scores on a Scale | — | 3.5 Scores on a Scale |
| Baseline Health Score | 9.3 scores on scale | 9.1 scores on scale | — | 9.2 scores on scale |
| Number of COVID-19 morbidities | 3.5 COVID-19 related morbidities | 2.4 COVID-19 related morbidities | — | 3 COVID-19 related morbidities |
| Number of COVID-19 symptom days prior to study entry | 8.5 days | 9.1 days | — | 10.6 days |
| Number of pre-existing Comorbidities | 3.7 Comorbidities | 4.7 Comorbidities | — | 4.2 Comorbidities |
| Number of pre-existing home medications | 3.8 Home medications | 4.8 Home medications | — | 4.4 Home medications |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 17 Participants | 32 Participants |
| Region of Enrollment United States | 10 Participants | 9 Participants | 25 Participants | 44 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 14 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 0 |
| other Total, other adverse events | 0 / 10 | 3 / 9 | 0 / 0 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 0 |
Outcome results
Primary
Measure of Daily Stool Frequency for Patients With COVID Treated With Bismuth
Number of bowel movements recorded over the 3 day study. Baseline (BL) /day1 + Day 2 + Day 3
Time frame: 3 days
Population: Data from 10 completed patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label BSS Completed Patients | Measure of Daily Stool Frequency for Patients With COVID Treated With Bismuth | 3 bowel movements | Standard Error 0.5 |
Secondary
Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP)
Salivary SARS-CoV2 measured daily. The final outcome is SARS-CoV2 status on day 3. Clearance of SARS-CoV2 ( a negative salivary SARS-CoV2 RT-LAMP test). or Remained SARS-CoV2+ ( a positive salivary SARS-CoV2. RT-LAMP test)
Time frame: Day 3 - or 48 hours after starting BSS
Population: These 10 patients completed BSS therapy and provided 3 days of saliva for RT-LAMP testing for presence or absence of SARS-CoV2
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label BSS Completed Patients | Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP) | Those who cleared salivary SARS-CoV2 | 5 Participants |
| Open Label BSS Completed Patients | Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP) | Those who remained salivary SARS-CoV2 positive | 5 Participants |
| SOC Control Group | Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP) | Those who cleared salivary SARS-CoV2 | 0 Participants |
| SOC Control Group | Salivary SARS-CoV2 Day 3 Status Using Reverse-transcription Loop-mediated Isothermal Amplification (RT-LAMP) | Those who remained salivary SARS-CoV2 positive | 0 Participants |
Post Hoc
Day 3 Composite 3 Symptom Score
The 3 symptom composite score was generated from 3 symptoms: Cough, Headache, and Fatigue. Each symptom was scored as such: 0 was not affected, 1 was little affected, 2 moderately affected, 3 severely affected. A composite score was generated using the score given for each individual symptom, ie. the sum of symptomatic score of Cough + symptomatic score of Headache + symptomatic score of Fatigue. The maximum and most symptomatic composite score could be 9 each day. The minimum score could be 0 . This score was calculated calculated for BL/day1, day 2 and day 3 . This outcome is the composite 3 symptom score on day 3.
Time frame: This is the day 3 composite score
Population: These 10 patients completed the open label BSS study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Open Label BSS Completed Patients | Day 3 Composite 3 Symptom Score | 1.4 score on a scale |
Post Hoc
Day 3 Composite 5 Symptom Score
The 5 symptom composite score was generated from 5 symptoms: Cough, Headache, Fatigue, Shortness of Breath, and Anosmia (no smell). Each symptom was scored as such: 0 was not affected, 1 was little affected, 2 moderately affected, 3 severely affected. A composite score was generated using the score given for each individual symptom, ie. the sum of symptomatic score of Cough + symptomatic score of Headache + symptomatic score of Fatigue + symptomatic score of Shortness of Breath + symptomatic score of anosmia. The maximum and most symptomatic composite score could be 15 each day. The minimum score could be 0. This score was calculated calculated for BL/day1, day 2 and day 3 . This outcome is the composite 5 symptom score on day 3.
Time frame: The score was taken at BL (baseline)/day 1, Day 2 ( 24 hours after BSS started ) and Day 3 (48 hours after BSS started). This Outcome is Day 3 score.
Population: Those 10 patients who completed BSS open label therapy
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Open Label BSS Completed Patients | Day 3 Composite 5 Symptom Score | 2.9 score on a scale |