A Randomized, Open Label, 2-Treatment Groups Clinical Trial Evaluating the Safety and Efficacy of 2-Deoxy-D-Glucose as an adjunctive therapy to standard of care, in comparison to standard of care alone, in the Acute Treatment of moderate to severe COVID -19 patients
Coronavirus as the cause of diseases classified elsewhere
Intervention / Comparator Agent
Type
Name
Details
Intervention
2-Deoxy-D-Glucose Oral Powder
45 mg/kg Morning + 18 mg/kg Evening as long as SoC is being administered, but no longer than discharge or Day 28 (whichever is earlier)
Comparator Agent
Standard of Care
Upto Day 28 discharge but no more than Day 28
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
1. Male, female and transgender patients aged ≥ 18 years and ≤ 65 years
2. Patients testing positive for SARS-CoV-2 by rRT-PCR on a nasopharyngeal or oropharyngeal swab
Note: A re-treated/ relapsed patient may be enrolled if he/she meets all of the following criteria:
a. Documented re-conversion on nasopharyngeal or oropharyngeal swab from negative to positive for SARS-CoV-2 OR nasopharyngeal or oropharyngeal swab continues to be positive for SARS-CoV-2 after previous treatment
AND
b. Clinical symptoms associated with COVID-19 (fever, cough, difficulty in breathing, fatigue, body ache, headache, diarrhea, nasal congestion) have either re-appeared after previous treatment OR continued to be present without improvement OR are aggravated
AND
c. Patient meet the below-mentioned criterion (# 3) for ‘moderate’ or ‘severe’ COVID-19 disease severity
3. Patients clinically assigned as ‘moderate’ (Pneumonia with no signs of severe disease, respiratory rate 15 to 30/minute, SpO2 90%-94%) or ‘severe’ (Severe Pneumonia with respiratory rate ≥30/minute and/or SpO2 < 90% in room air) but not critically ill (acute respiratory distress syndrome [ARDS], multi organ failure or septic shock)
Note: The severity is as defined by the Guidance document on appropriate management of suspect/confirmed cases of COVID-19 published by the Ministry of Health & Family Welfare on 07 Apr 2020.
4. Females should have a negative serum pregnancy test at baseline; female patients of child bearing potential should either be abstinent or comply with one or more contraception methods (with low user dependency and failure rate of <1%) for the entire duration of the treatment period and until 90 days after receiving the last dose of study treatment
5. Able and willing to provide informed consent
6. Able to understand the trial requirements and comply with trial medications and assessments in the opinion of the Investigator
7. Agrees not to participate in other clinical studies within 30 days after the last administration of the study treatment
ExclusionCriteria
Details
1. Critically ill patients, defined as those who are candidates for endotracheal intubation and invasive mechanical ventilation and those with ARDS, septic shock or multi-organ failure at baseline
2. Patients with previous history of hypersensitivity or a contra-indication to the IMP 2-deoxy-D-glucose or the imaging marker Fludeoxyglucose (FDG)
3. Patients with history of one or more known comorbidities at baseline:
a. Cardiac Failure
b. Prior or concurrent ischemic coronary artery disease (CAD): angina pectoris, history of myocardial infarction or documented silent ischemia or coronary artery vasospasm, including Prinzmetal’s angina
c. Cardiac conduction delay (QTc > 500 msec) or taking any prescription medications known to prolong QT interval
d. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
e. Diabetes Mellitus or any condition predisposing to hypoglycaemia
f. Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD)
g. Asthma or Interstitial Lung Disease
h. Malignancy
i. Other severe underlying diseases (e.g., active bleeding, blood dyscrasias, severe malnutrition)
j. Presence of any contra-indication to the chosen Standard of Care treatment
4. Patients who are receiving drugs known to prolong the QT interval of heart including hydroxychloroquine or azithromycin OR are expected to require treatment with the same during the treatment period in the study (as of baseline assessment).
5. Received biological therapy (especially, experimental ACE-2 decoy or decoy receptor/monoclonal antibody against interleukin-6, interferon alpha) or convalescent plasma (for COVID-19 treatment) in the 90 days (prior to baseline visit).
6. Any other therapy which may confound the interpretation of efficacy outcomes or increase safety risks to patients. This includes patients receiving other investigational therapies for COVID-19.
7. Inability to take oral medication.
8. Patients with malabsorption or gastrointestinal abnormalities which may affect drug absorption
9. Body Weight < 45 kg or >130 kg
10. Female patients who are pregnant or lactating
11. Patients who have received organ transplantation in the last 6 months or currently on immunosuppressive therapy (eg. Methotrexate, Cyclosporine, etc.)
12. Patients who are contemplating surgery/ female patients contemplating a pregnancy within 90 days after scheduled end of study treatment
13. Patients who are not suitable to participate in the study based on the Investigator’s judgeme
Day 3,7,10,14 and 28 (until patient reaches score of 4 or lower on 10 point ordinal scale for clinical status or discharge, whichever is earlier).
Secondary Outcome
Outcome
TimePoints
Change from baseline in mean viral load (determined by rRT-PCR on nasopharyngeal/oropharyngeal swab)
Days 3, 7, 10, 14 and 28
Changes of parameters at each assessment during the study/follow-up period, compared to baseline for:
o Vital signs: body temperature, heart rate, respiratory rate, systolic/diastolic blood pressure and oxygen saturation.
o Clinical laboratory assessments: hematology, serum chemistry, urinalysis.
o 12-lead ECG: Changes in heart rate, PR, QRS, QT and QTcB intervals.
Days 3, 7, 10, 14 and 28
Mean change from baseline in NEWS-2 score
Days 3, 7, 14, 21 and 28 (or discharge, if discharge happens before)
Mean change from baseline in patient’s clinical status on a 10-point ordinal scale (SOLIDARITY trial)
Days 3, 7, 14, 21 and 28 (or discharge, if discharge happens before)
Mean/ median time (no. of days) from start of study treatment to clinical status score improvement by 1 and by 2 (from baseline) on the 10-point ordinal scale used in the SOLIDARITY trial by WHO
Day 1 to Day 28
Mean/ median time (no. of days) the patient is:
a. Managed in intensive care unit
b. On Oxygen supplementation
c. On Invasive mechanical ventilation
Day 28
Mean/ Median Time to achieve symptom improvement of at least 30% in the COVID-19 symptoms sum score from baseline
Day 14
Mean/median time (no. of days) from start of study treatment to discharge from the ‘isolation ward’ of the COVID management facility.
Day 1 to Day 28
Mean/Median time (no. of days) to negative conversion (of detectable SARS-CoV-2 viral RNA) on nasopharyngeal swab from day of first treatment intake
Day 1 to Day 28
Mean/median time (no. of days) to
a. Management in intensive care unit
b. Oxygen supplementation
c. Invasive mechanical ventilation
Day 28
Number (and percentage) of patients reporting treatment emergent adverse events (TEAEs) (by MedDRA system organ class and preferred term)
Days 3, 7, 10, 14 and 28
Percentage of patients dying due to COVID-19 complication
Day 1 to Day 28
Percentage of patients requiring, until Day 28 of treatment:
a. Management in intensive care unit (ICU)
b. Oxygen supplementation
c. Invasive mechanical ventilation
Day 28
Percentage of patients showing negative conversion (of detectable SARS-CoV-2 viral RNA) on nasopharyngeal/oropharyngeal swab
Day 10 and Day 28
Percentage of patients who achieve the endpoint of Clinical improvement
COVID-19 is currently a major global public health crisis and in the absence of an effective vaccine and ‘herd’ immunity, there are no known interventions for effectively dealing with this pandemic (other than broad public-health measures like physical distancing and containment). At an individual COVID-19 patient level, there is a lack of proven specific treatment options that improve symptoms, influence disease severity progression and clinical outcomes or aid the treating physician in better patient management. Different medicines and medicinal systems are being explored to find remedial measures for this new infection. Antiviral drugs, and other antimicrobial agents are being evaluated and being utilized off-label in treating patients, largely those with more severe COVID-19. However, no breakthrough has been achieved to date either in curtailing the pandemic or improving patient outcomes.
2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, is known to inhibit the growth of neoplastic cells in vitro and in vivo. While 2-DG is not an approved drug, it has been studied in 218 clinical trials for the treatment of various cancers globally. 2-DG has not been evaluated in the acute treatment of moderate to severe COVID-19. However, based on mechanistic and in-vitro-evidence (see below) as well efficacy seen in the interventional clinical studies in malignancies and genital herpes, the Sponsors believe that 2-DG could be developed for the specific treatment of patients with COVID-19 disease in conjunction with other anti-viral therapies.
2-DG was chosen based on its in vitro inhibition potential (EC50 = 1.0 mM, EC90 = 3.7 mM; supernatant) towards SARS-CoV-2 from the studies conducted by Institute of Nuclear Medicine & Allied Sciences (INMAS), Delhi of the Defence Research and Development Organization (DRDO) at Centre for Cellular and Molecular Biology, Hyderabad. The Sponsor of this study, INMAS, DRDO, Ministry of Defence, Govt of India, was responsible for genesis of this hypothesis and testing of efficacy of 2-DG against SARS-CoV2. These effective concentrations are within the range that can be achieved in human plasma upon oral dosing of 63 mg/kg/day.
Moreover, Positron Emission Tomography (PET) with the radiotracer, 18FDG (Fludeoxyglucose, an analog of 2-DG) has shown accumulation of the radiolabel in the inflamed lungs of COVID-19 patients, due to high metabolic activity induced by the coronavirus infection. Dr Reddy’s believes that this phenomenon could potentially result in a preferential and disproportionately high accumulation of 2-DG in inflamed lung tissue of COVID-19 patients thereby leading to starvation in the lung cells, which in turn would lead to inhibition of viral replication.
