The study design is prospective, double blind, placebo-controlled trial aims to examine the
effect of pioglitazone on inflammatory markers and clinical outcome in T2DM patients infected
with COVID-19. 1506 T2DM patients with proven COVID-19 infection (positive swab) and at least
one COVID-19 symptom will be randomized to receive in a double blind fashion pioglitazone or
placebo for 28 days. Inflammatory response and a composite of clinical outcome will be
measured at 3, 7, 14, 21 and 28 days (or time of discharge) after initiating therapy.

Study Design

1. Upon admission, subjects will be evaluated for inclusion and exclusion criteria.
Eligible subjects will be consented.

2. After consenting, medical history and vital signs will be done including ECG and chest
X-ray.

3. Blood for the following parameters (Panel 1, which are routinely measured for the
management of COVID-19 patients) will be sent for measurement in the clinical lab: CBC,
Full chemistry panel including LFT and RFT, lipid profile, blood gases, HbA1c, hsCRP,
Troponin I, coagulation screen, D-Dimers, and Ferritin.

Study Intervention:

After completing baseline studies, subjects will be randomized in a double-blind fashion to
receive: (1) pioglitazone, or (2) placebo. The study intervention will be introduced every
morning at the same time for 4 weeks.

Because previous studies from Kuwait demonstrated that the mean hospitalization period for
COVID-19 patients in Al-Jaber hospitals is 24 days.

Patient will be randomized based upon the following parameters: age, gender, BMI, baseline
medications, background health conditions, diabetes duration, and respiratory rate. Each
parameter will be monitored amongst both groups and the distribution of patients according to
each parameter will be evenly distributed amongst the two treatment groups.

Pioglitazone will be started at 45 mg/day dose for 10 days, after 10 days, the dose will be
reduced to 30 mg/day to minimize possible adverse events. The treatment will be continued for
4 weeks (28 days) total.

If during hospitalization, patient condition requires admission to ICU, respiratory support,
or develops an increase in plasma troponin I levels (incidence of primary outcomes),
pioglitazone/placebo therapy will be continued for the entire 4 weeks. Patient outcome will
be evaluated weekly until end of week 4.

If patient condition is improved and patients is eligible for discharge (become asymptomatic
plus O2 saturation >94% on room air) and he is discharged home prior to 4 weeks, blood tests
will be drawn on discharge day, and patient will continue therapy at home to complete 4 week
treatment period. At 28 days, a phone visit will be made to check on patient outcome. If
discharged patients is readmitted due to deterioration in his clinical condition, the 28 day
count will be considered since randomization.

Concomitant COVID-19 Therapy

1. Patients will receive standard of care for COVID-19 disease according to local
guidelines. Other anti-inflammatory therapy or antiviral therapy for COVID-19 used in
the medical center will be introduced to all patients unless prohibited by exclusion
criteria. Reason for administration, administration dose, start date and duration of all
medications introduced during hospitalization for COVID-19 therapy will be recorded.

2. Therapy for other background patient condition, e.g. blood pressure, cholesterol, etc.
will be continued as per local guidelines.

3. If patient clinical condition through hospitalization precludes the use of pioglitazone
(primarily due to fluid retention), the study intervention will be discontinued and
distally acting diuretics (Aldactone 25 mg/day) will be started to reverse fluid
retention.

4. If patient is transferred to other medical facility due to space issues (eg. transfer to
field hospital), the patient will continue to be enrolled in the study, will receive
study intervention and followed according to protocol in the other medical facility
until discharge from the other medical facility.

Study End The study will end at end of week 4. Patients will be evaluated at end of week 4,
and end of study data collection will be done, after which study intervention will be
discontinued.

Measurement of compliance:

Study intervention will be administered in hospitalized patients or patients at other medical
facilities under the supervision of medical team. If patients are discharged, they will
continue therapy at home to complete the 4-week treatment period. Discharged patients will
return to end of study visit at week 4, pill count will be performed at study end visit to
evaluate patient compliance.

Glucose Control:

After completing the medical history, physical examination, and blood draws, if the patient
receives SGLT2 inhibitor or metformin as antihyperglycemic therapy, they will be discontinued
to reduce the risk of ketoacidosis and lactic acidosis, respectively. Sulfonylurea also will
be discontinued to reduce the risk of hypoglycemia.

Patients who are not taking insulin for their antihyperglycemic therapy will be started on
insulin. (see instructions below Table 1). Subjects receiving insulin therapy, if they
receive basal/bolus insulin, the insulin dose will be adjusted to achieve the glucose
treatment goals (140-180 mg/dl, 7.8-10 mM). subjects receiving premixed insulin will be
switched to basal/bolus insulin as described below.

Daily blood glucose values will be measured every morning and according to local glucose
monitoring policy according to patient needs.

Table 1: Instructions for starting insulin therapy

1. Discontinue oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin,
SGLT2 inhibitors) on admission. Patients receiving DPP-4 inhibitors or GLP-1 RA will be
allowed to continue these agents according to the treating physician discretion.

2. Starting insulin total daily dose (TDD): 0.5 units per kg of body weight. If patient is
≥ 70 years of age and/or with a serum creatinine ≥ 176 umol/l, reduce insulin TDD to 0.3
units per kg of body weight

3. Give half of total daily dose as insulin glargine and half as preprandial insulin

4. Administer insulin glargine once daily, at the same time of the day every day

5. Administer preprandial insulin in three equally divided doses before each meal.

6. If patient is unable to eat, hold the preprandial insulin

7. If patient receives GLP-1 RA as part of his diabetes management and you decide to
continue GLP-1 RA therapy, hold the preprandial insulin

8. Adjust the glargine dose and preprandial insulin based upon the daily measured blood
glucose levels to achieve a plasma glucose concentration 140-180 mg/dl (7.8-10 mM).

9. If patient's clinical condition requires admission to ICU, continues intravenous insulin
infusion according to the protocol routinely used in the ICU is advised.

Other chronic diseases, including blood pressure, heart disease, lung disease, and all other
medical conditions will be treated according to local guidelines or local treatment protocols
for COVID-19 patients.

In hospital Follow-up:

Consistent with in patient care, daily medical history and physical examination will be done.
The following parameters will be daily measured:

1. Mental status

2. Fever

3. Respiratory rate and use of auxiliary muscles

4. Oxygen saturation at room air or volume of oxygen flow rate needed to maintain oxygen
saturation >95% (in patients without mechanical ventilation)

5. Heart rate and rhythm

6. Blood pressure Blood glucose levels will be measured according to hospital policy and
insulin dose is adjusted to maintain blood glucose levels at the treatment range
(140-180 mg/dl, 7.8-10 mM).

A complete follow-up visit with blood tests will be done at day 3,7, 14, 21, and 28.

All baseline Blood samples (Panel 1 and Panel 2) will be repeated at each follow-up visit. If
patient clinical conditions are improved and the caring physician decided to discharge the
patient home before the end of the week, all repeat blood samples will be done prior to
discharge even if previous blood sample was less than one week. If patient will be
transferred to a different medical facility or hospital to continue medical care, blood
sample collection will be continued until patient is no longer part of the research protocol.

Criteria for discontinuation of study intervention:

The study intervention will be discontinued if:

1. Allergy to the study drug develops

2. Development of pulmonary congestion (based upon chest X-ray) requiring diuretic therapy

3. Peripheral edema requiring diuretic therapy

4. Withdraw consent