Clinical trial NCT04729140: An Outpatient Clinical Trial Using Ivermectin and Doxycycline in COVID-19 Positive Patients at High Risk to Prevent COVID-19 Related Hospitalization
Official title: A Randomized Double-blinded Placebo-controlled Outpatient Clinical Trial in High Risk Population Confirmed COVID-19 Patients Using Ivermectin and Doxycycline to Prevent COVID-19 Illness-related Hospitalization (COVIVER-OUT PLUS)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Covid19
Keywords: COVID 19
Ivermectin
Doxycycline
Lead sponsor: Max Health, Subsero Health
Sponsor class: OTHER
First posted: 2021-01-28
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded, prospective, placebo controlled outpatient randomized clinical trial.
Primary purpose: TREATMENT

Brief summary: The purpose of this Clinical trial is to explore the therapeutic benefits of Ivermectin and Doxycycline in different combinations in high risk patients diagnosed with COVID-19.

Detailed description: Purpose of the study:

The purpose of this Clinical trial is to explore the therapeutic benefits of Ivermectin and Doxycycline in different combinations. The investigators are studying known medications at already FDA approved dosages for therapeutic benefit. The investigators are not seeking new indications for these medications.

Null Hypothesis:

The investigators hypothesize that treating high-risk populations positive for COVID-19 illness with Ivermectin, Doxycycline, or Ivermectin only in the outpatient setting will decrease hospitalizations related to COVID-19 illness in comparison with Placebo.

Sample Size: Minimum of 50 high risk COVID 19 positive patients who volunteer and provide consent to participate in this study to be placed in three different groups (A,B,C). Subjects are to be randomized 1:1:1 and enrolled in sequential order to Group A, then B, then C as they enroll. This distribution pattern will be followed for the entirety of the study.

Group A: Ivermectin plus Doxycycline Group B: Ivermectin plus Placebo Group C: Placebo plus Placebo

Drug Dosing schedule:

Group A: Ivermectin 200 mcg/kg on day 1 and day 2-plus doxycycline 100 mg tablets twice a day for seven days

Group B: Ivermectin 200 mcg/kg on day 1 and day 2-plus placebo tablet twice a day for seven days

Group C: Placebo (number of tablets according to weight) plus placebo twice a day for seven days

Body Weight (kg) Table for tablets of Ivermectin

15-24 kg 1 tablet 25-35 kg 2 tablets 36-50 kg 3 tablets 51-65 kg 4 tablets 66-79 kg 5 tablets 80-109 kg 6 tablets \>110 kg 7 tablets

The designated pharmacy will provide pre-packed treatment to patients based on the order of enrollment to the clinical trial.

Methods:

(A) Upon diagnosis of COVID-19 with NAAT-PCR or Rapid Antigen Test for SARS-COV 2, patients will be evaluated by their primary care physician who will consider the health risk of patients and provide all alternatives. Primary care physicians will recommend these patients to a treatment hotline number. Patients can also self refer to the treatment hot line. Patients will call this provided hotline number, and if they wish to be a part of the above said clinical trial, it will connect them to the Principal Investigator's (Dr Werther Marciales) Team. Based on inclusion and exclusion criteria, patients will be assigned to one of three different study groups outlined above. Each participant in all randomized groups will receive treatment as specified above as soon as the patient signs consent and agrees to participate in said clinical trial. Patient's subjective data including but not limited to age, gender, height, weight, detailed medical history, or any objective data will be collected and kept confidential.

(B) Patients will undergo blood work (CBC, CMP, Ferritin, D-dimer, CRP, CK, PT/INR, PTT and Fibrinogen, Interleukin 6 level,TNF alpha level, IL6 receptor level and TNF alpha receptor level) at baseline. Blood work will be repeated on days 7 and 14. These medications used in the clinical study will have a good safety profile, which has been tested over a period of time. All patients enrolled in the trial will be thoroughly evaluated prior to detailed history, especially regarding home medications, and severe co-morbid conditions as listed in the exclusion criteria.

(C) During the clinical trial, the study doctor, or the subject's primary care provider will be involved in treatment of subjects if and when there are any adverse reactions or if subjects need additional care. If a patient's COVD-19 relayed symptoms worsen then, he/she would be admitted to the hospital for further care, including mechanical ventilation if required. These patients clinical data will be followed for the remainder of he hospitalization. A patient admitted to the hospital for COVID-19 related illness will be considered to reach outcome.

Criteria for admission of confirmed COVID-19:

A patient must have COVID-19 illness and at least one of the following two conditions:

1. At least 2 of the CURB-65 criteria
2. SpO2 \<93% on room air or a 4% decrease from baseline

CURB 65 criteria

1. Confusion of new onset
2. Blood Urea Nitrogen greater then 7 mmol/L (19 mg/dl)
3. Respiratory rate of 30 breaths per minute or greater
4. Blood Pressure less then 90 mm Hg systolic or 60 mm Hg diastolic
5. Age 65 or older

(D) Patients will be advised to quarantine themselves and record their temperature twice daily and maintain a home log. Patients will obtain a pulse oximeter to monitor their oxygen levels at least twice a day. Patients will also be submitted to symptoms questionnaire or ARDS questionnaire either in person or over telephone or through televist twice a week for total of five weeks.

(E) All treatment groups will also be monitored for any adverse events related to medication therapy during treatment and for 4 weeks thereafter on a twice a week basis using ADR Monitoring form. All moderate and severe adverse drug reactions will be notified to the principal investigator for immediate actions, which might include discontinuation of therapy after establishing a causal relationship. All adverse drug reactions will be recorded and reported to the FDA using Form 3500, which will be faxed to 1 800 FDA 0178. Due to the severe nature of transmissibility of COVID-19 and the importance of minimizing human interaction and preservation of Personal Protective Equipment, patients will be followed either in person, telephonically or via Televisit. Exclusion Criteria will mitigate the risk of involving patients susceptible to side effects of study treatment medications.

Data Analysis:

The total sample size is estimated at 150 participants (Minimum 50 patients in each group). The one-way analysis of variance (ANOVA) will compare group differences at baseline, midpoint, and endpoint. Data analysis will be carried out using statistical package for the social sciences software (SPSS). Interim data analysis will be performed at three different levels of the number of participants starting at sample size 20, 30 and 50. If no significant findings are obtained from the data at N=50, then it will add more participants to the study to achieve statistical significance. Sponsor and Principal Investigator will defer data analysis to a statistician. A Data Monitoring Committee (DMC) is going to be established in order to review accumulating trial data by treatment group in order to monitor patient safety and efficacy, ensure validity and integrity of the trial and make benefit-risk assessment. This is going to be conducted by a third party external DMC.

Ethical Considerations:

Informed consent will be obtained via phone, telecommunications, or in person and a copy of the consent will be sent to the subjects via postal mail, email or both. All information will be kept confidential. For research records, name, social security number, address, or phone number will not identify patients. In the event of any publication or presentation resulting from the research, no personally identifiable information will be shared. The investigators will keep the patients participation in the research study confidential to the extent permitted by law. Patient identifiers might be removed from data and, after such removal, the data could be used for future research or distributed to another investigator for future studies without additional informed consent from the subject.

Resources:

There is no funding available at this time, and the study will be self sponsored by MAX HEALTH.

Compensation:

There is no compensation offered as part of participation in this study.

Cost:

Patients will be charged for any services that are performed as part of their clinical care. Patients will not be compensated for travel or time. Patients are required to get their medication (s) used in the clinical trial from a dedicated pharmacy. Study drugs will be provided to the patients at no cost to the patient.

Removal from this study:

The patient may elect to withdraw from the study at any point. During the clinical trial, if a patients COVID-19 related symptoms worsen, then they would admitted to the hospital for further care, including mechanical ventilation if required, and the clinical data from this subset of patients will not be used for statistical consideration of this study. Still, these patients clinical data will be followed for the remainder of the hospitalization.

Eligibility criteria: Inclusion Criteria:

* Age greater than or equal to 18
* Willing and able to provide verbal /telephonic/Personal or computer based Informed Consent
* Experiencing symptoms of COVID-19 illness and tested positive for SARS CoV-2 with either PCR, NAAT or antigen testing
* Residents in a Nursing Home or long-term care facility
* Immunocompromised state, including solid organ transplant, HIV infection, other immune deficiency, immunosuppressant medication including systemic corticosteroids
* Chronic lung disease, including Chronic Obstructive Pulmonary Disease (COPD), moderate to severe asthma, cystic fibrosis, pulmonary fibrosis
* Cardiovascular Disease
* Cancer
* Hypertension
* Obesity (body mass index \[BMI greater then or equal to 30 kg/m\^2\]
* Diabetes Mellitus
* Chronic Kidney Disease
* Chronic Liver Disease
* Cerebrovascular Disease
* Neurological Disorders including dementia
* Tobacco use disorders
* Hematologic disorders, including sickle cell disease and thalassemia

We are also interested in including a vital population to protect, considered essential workers who may not fit into the above inclusion criteria:

* Health care professionals and firefighters.
* Government officials or employees.
* Students and teachers.
* Law enforcement agents and personnel.
* Individuals who live with, and cannot isolate, from any of the above groups.

Exclusion Criteria:

* Participants under the age of 18
* Received any COVID vaccine within the last 30 days
* Contraindications to Ivermectin or Doxycycline
* History of Seizure Disorder or Epilepsy
* History of Myocardial Infarction or Heart Attack within the last one month
* Already receiving Ivermectin or Doxycycline for treatment of any other disease or disorder
* Allergies to Ivermectin or Doxycycline including angioedema, severe asthma, exfoliative dermatitis, Steven Jonson syndrome or psoriasis
* History of angioedema, exfoliative dermatitis, Steven Johnson syndrome, psoriasis
* Currently Pregnant or planning to conceive soon
* Breastfeeding
* History of prior Clostridium Difficile infection

Primary outcomes:
measure: Decreased admission rate to the hospital secondary to respiratory illness related to COVID-19
timeFrame: 5 weeks
Secondary outcomes:
measure: Decrease in total duration of symptoms secondary to respiratory illness related to COVID-19
timeFrame: 5 weeks
measure: Assessment of White Blood Cell Count
timeFrame: 2 weeks
measure: Assessment of Hemoglobin level
timeFrame: 2 weeks
measure: Assessment of Hematocrit level
timeFrame: 2 weeks
measure: Assessment of Platelet Count
timeFrame: 2 weeks
measure: Assessment of Sodium level
timeFrame: 2 weeks
measure: Assessment of Potassium level
timeFrame: 2 weeks
measure: Assessment of Chloride level
timeFrame: 2 weeks
measure: Assessment of Carbon Dioxide level
timeFrame: 2 weeks
measure: Assessment of Blood Urea Nitrogen level
timeFrame: 2 weeks
measure: Assessment of Creatinine level
timeFrame: 2 weeks
measure: Assessment of Calcium level
timeFrame: 2 weeks
measure: Assessment of Glucose level
timeFrame: 2 weeks
measure: Assessment of Total Bilirubin level
timeFrame: 2 weeks
measure: Assessment of Total Protein level
timeFrame: 2 weeks
measure: Assessment of Albumin level
timeFrame: 2 weeks
measure: Assessment of Aspartate Aminotransferase level
timeFrame: 2 weeks
measure: Assessment of Alanine Aminotransferase level
timeFrame: 2 weeks
measure: Assessment of Alkaline Phosphatase level
timeFrame: 2 weeks
measure: Assessment of Ferritin
timeFrame: 2 weeks
measure: Assessment of D-dimer
timeFrame: 2 weeks
measure: Assessment of Creatine Phosphokinase
timeFrame: 2 weeks
measure: Assessment of C-Reactive Protein
timeFrame: 2 weeks
measure: Assessment of Prothrombin Time and International Normalized Ratio
timeFrame: 2 weeks
measure: Assessment of activated Partial Thromboplastin Time
timeFrame: 2 weeks
measure: Assessment of Fibrinogen Activity
timeFrame: 2 weeks
measure: Assessment of Interleukin 6 level
timeFrame: 2 weeks
measure: Assessment of Interleukin 6 receptor level
timeFrame: 2 weeks
measure: Assessment of Tumor Necrosis Factor Alpha level
timeFrame: 2 weeks
measure: Assessment of Tumor Necrosis Factor Alpha Receptor level
timeFrame: 2 weeks
measure: Mortality
timeFrame: 5 weeks
measure: Measurement of Participants with Medication Side Effects
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Shortness of Breath or Changes in Shortness of Breath Severity
timeFrame: 5 weeks
measure: Measurement of Participants Pulse Oximetry readings on room air
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Red Eyes or Changes in Red Eyes Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Chills or Changes in Chills Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Runny Nose or Changes in Runny Nose Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Sore Throat or Changes in Sore Throat Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Loss of Smell or Changes in Severity of in Loss of Smell
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Loss of Taste or Changes in Severity of Loss of Taste
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Body Aches or Body Pains or Changes in Body Aches or Body Pains Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Diarrhea or Changes in Diarrhea Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Headaches or Changes in Headaches Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Anxiety or Changes in Anxiety Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Fatigue or Changes in Fatigue Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Trouble Concentrating or Changes in Trouble Concentrating Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Cough or Changes in Cough Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Vomiting or Changes in Vomiting Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Nausea or Changes in Nausea Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Feelings of Hopelessness or Changes in Feelings of Hopelessness severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset feelings of Depression or Changes in feelings of Depression severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Fever or Changes in Fever Severity
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Moving Slowly or Changes in the Severity of Moving Slowly
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Speaking Slowly or Changes in the Severity of Speaking Slowly
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Feelings of Restlessness or Changes in the Severity of Feelings of Restlessness
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Thoughts of Better Off Being Dead or Changes in the Severity of Thoughts of Better Off Being Dead
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Thoughts of Hurting Yourself or Changes in the Severity of Thoughts of Hurting Yourself
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Loss of Interest in Doing Things or Changes in the Severity of Loss of Interest in Doing Things
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Loss of Pleasure in Doing Things or Changes in the Severity of Loss of Pleasure in Doing Things
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Trouble Falling Asleep or Changes in the Severity of Trouble Falling Asleep
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Trouble Staying Asleep or Changes in the Severity of Trouble Staying Asleep
timeFrame: 5 weeks
measure: Measurement of Participants with new onset Unmentioned Negative Impacts of COVID 19 infection or Changes in the Severity of these Negative Impacts of COVID 19 infection
timeFrame: 5 weeks
Other outcomes:
Locations:
city: Sarasota
country: United States
facility: MAX HEALTH, Subsero Health 2055 Wood Street, Suite 100
state: Florida
Study officials:
affiliation: Clinical Trial Principal Investigator
name: Werther Marciales, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: sub Clinical Trial Prinicipal Investigator
name: Ryan Salom
role: PRINCIPAL_INVESTIGATOR
affiliation: sub Clinical Trial Prinicipal Investigator
name: Faheem Ahmad, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Investigator
name: Divisha Sharma, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Investigator
name: Nicholas Guy Ross, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Investogator
name: Terry Fredeking
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Trial Investogator
name: Michael Ricciardi, PhD
role: PRINCIPAL_INVESTIGATOR
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