Clinical trial NCT04475588
Conditions: Acute Respiratory Distress Syndrome Cytokine Release Syndrome Covid19
Sponsor: Biocon Limited
Start date: 2020-05-01; Completion date: 2020-07-07
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, Parallel Group, Active Controlled Trial

Detailed description:
This is a Multi-Centric, Open label, Two Arm Randomized, Phase 2 Study.

All eligible patients entering into the study will be randomized in 2:1 ratio to receive the treatment A (Best supportive care + Itolizumab) / B (Best supportive care) respectively. Each patient will undergo the treatment based on their assigned treatment for a month along with battery of tests that includes, but not limited to, cytokines and chemokine, along with recording of TLC; DLC, ANC, ALC; Platelet count; S. creatinine; T.Bilirubin; morning Vitals -pulse, BP, RR; Temperature, PaO2/FiO2, MAP, GCS.

As Itolizumab is an investigational drug, the benefit to COVID-19 patients experiencing complications such as Cytokine Release Syndrome is not known. However, findings from this study may be beneficial to the society at a large at the National and International Level.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Itolizumab IV infusion intervention 2: Best supportive care (BSC)
Intervention descriptions: intervention 1: First dose of 1.6 mg/kg dose iv infusion, , investigator discretion to continue with 1.6 mg/kg dose every 2 weeks or 0.8 mg/kg weekly regimen up to 4 weeks.

BSC: similar to Arm B intervention 2: Best supportive care (BSC) included drugs like antivirals, antibiotics, Hydroxychloroquine, oxygen therapy, LMWH, Steroids, Vitamins and Zinc

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
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Date 04-Jun-2020 
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Page 1 of 49 
 
 
 
 
 
 
Clinical Study Protocol 
 
 
 
Study Title: A Multi-Centric, Open label, Two Arm Randomized, Pivotal Phase 
2 Trial to Study the Efficacy and Safety of Itolizumab in COVID-19 
Complications 
 
 
 
Protocol Number: 
ITOLI-C19-02-I-00 
Version Number and 
Date 
5.0, Dated 04-Jun-2020 
Superseded Version and 
Date 
4.0, Dated 20-May-2020 
Investigational Product 
Itolizumab (ALZUMAb™) 
Phase of Development 
Pivotal Phase 2 
Study type 
Prospective randomized two arm study 
CTRI Number: 
CTRI/2020/05/024959 
Sponsor 
Biocon Biologics India Limited, Biocon House, Semicon Park, 
Bengaluru- 560100, Karnataka, India 
 
 
 
 
The study information described in this protocol will be performed according to the ethical principles described in 
the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), the International 
Council for Harmonisation Good Clinical Practice (ICH GCP) E6(R2), and New Drugs and Clinical Trials 2019 
issued by the Government of India. 


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1. Investigator’s Declaration 
 
Title: A Multi-Centric, Open label, Two Arm Randomized, Pivotal Phase 2 Trial to Study the 
Efficacy and Safety of Itolizumab in COVID-19 Complications 
 
 
Study Drug: ALZUMAbTM (Itolizumab injection) 
 
I, the undersigned have read and understood this protocol and hereby agree to conduct the study in 
accordance with this protocol and to comply with all requirements regarding the obligations of 
investigators and all other pertinent requirements of the ICH-E6 (R2) ‘Guidance on Good Clinical 
Practice’, Indian Good Clinical Practices and New Drugs and Clinical Trials 2019. 
 
Appropriate signatories at this site have signed the Investigator Agreement. As the Site Principal 
Investigator, I agree to: 
 
• Comply with any authorized protocol amendments, formal instructions and training; 
• Maintain local ethics committee approval for this protocol and related consent materials; 
• Maintain medical records to document study data, including supplemental records, 
worksheets or notes with study data; 
• Promptly submit adverse event reports as per post marketing reporting requirements; 
• Ensure that only coded study identifier(s) are associated with submitted study data, and that 
personally-identifying information (e.g., names, address, etc.) are not transmitted to other 
parties. 
 
I further agree to ensure that all associates assisting in the conduct of this study are informed 
regarding their obligations. 
 
Investigator’s Name: 
 
 
Investigator’s Affiliations: 
 
 
 
Investigator’s Signature with Date: 


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2. Sponsor’s Signature 
This protocol reflects the Sponsor’s current knowledge of investigational product- itolizumab as 
applicable to this study. It has been designed to achieve the stated objectives whilst minimizing 
exposure to, and risk from, both the products being used and the assessments. The protocol has 
been designed according to the principles of the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical 
Practice (GCP), Good Clinical Practices for Clinical Research in India published by Central Drugs 
Standard Control Organization, Indian Council of Medical Research guidelines for biomedical 
research on human subjects and the Declaration of Helsinki. It has undergone both medical and 
scientific review by the Sponsor. 
• We hereby agree to conduct the study in accordance with this protocol and the above-mentioned 
guidance/ regulation. 
• We agree to comply with all relevant standard operating procedures (SOP) required for the 
conduct of this study. 
• We further agree to ensure that all associates assisting in the conduct of study are informed 
regarding their obligations. 
 
 
 
 
Reviewed and Approved by: 
Sandeep 
 
Digitally signed by 
Sandeep Nilkanth Athalye 
Nilkanth Athalye Date: 2020.06.04 14:16:59 
+05'30' 
Sandeep Nilkanth Athalye, MBBS, MS 
Date: 
Head, Clinical Development and Medical Affairs 
Biocon Biologics India Limited, Bengalu u 


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Contents 
1. 
Investigator’s Declaration ...................................................................................................................... 2 
2. 
Sponsor’s Signature ................................................................................................................................ 3 
3. 
Background ............................................................................................................................................. 6 
Why CD6? ....................................................................................................................................................... 6 
CD6 and viruses .............................................................................................................................................. 6 
Why Itolizumab? ............................................................................................................................................ 6 
Hypothesis ....................................................................................................................................................... 7 
Summary of Clinical Safety with Itolizumab: .............................................................................................. 7 
4. 
Objectives ................................................................................................................................................ 8 
Primary Objectives: ........................................................................................................................................ 8 
Secondary Objectives ..................................................................................................................................... 8 
5. 
Outcome Measures ................................................................................................................................. 8 
Primary Outcome Measures: ......................................................................................................................... 8 
Secondary Outcome Measures: ..................................................................................................................... 9 
6. 
Population .............................................................................................................................................. 10 
Inclusion Criteria .......................................................................................................................................... 10 
Exclusion Criteria ......................................................................................................................................... 10 
Planned number of subjects ......................................................................................................................... 11 
Approximate number of sites: ..................................................................................................................... 11 
7. 
Treatment .............................................................................................................................................. 11 
Treatment Intervention and Dose ............................................................................................................... 11 
Dosing, Handling and Storage of Itolizumab ............................................................................................. 12 
8. 
Assessments ........................................................................................................................................... 14 
8.1 Schedule of Study Visits and Procedures ...................................................................................... 14 
8.2 Laboratory Procedures ................................................................................................................... 16 
Collection of Biomarker Samples: ........................................................................................................... 16 
Blood sample collections and handling instructions .......................................................................... 16 
9. 
Safety Monitoring ................................................................................................................................. 17 
Adverse Events and Safety Reporting ......................................................................................................... 17 
10. 
Data Handling Procedures .............................................................................................................. 18 
Source Documents..................................................................................................................................... 18 
Location of Data ........................................................................................................................................ 18 
11. 
Administrative Procedures ............................................................................................................. 18 
Ethics and Good Clinical Practice ........................................................................................................... 18 


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12. 
References ......................................................................................................................................... 20 
13. 
Appendices........................................................................................................................................ 22 
Appendix 1: World Medical Association Declaration of Helsinki-Ethical Principles for Medical 
Research on Human Patients ................................................................................................................... 22 
Appendix 2: Informed Consent Form ..................................................................................................... 29 
Appendix 3: Adverse Event Definitions and Safety Reporting for Investigators (as per requirements 
for marketed products)............................................................................................................................. 31 
a. 
Definitions ......................................................................................................................................... 31 
b. 
Classification of Adverse Events ....................................................................................................... 32 
c. 
Clarification in Reporting of Deaths .................................................................................................. 33 
d. 
Causality of the adverse event ........................................................................................................... 33 
e. 
Laboratory Abnormalities .................................................................................................................. 34 
f. 
Documentation of Adverse Events .................................................................................................... 34 
g. 
Follow-up of Adverse Events and Serious Adverse Events ............................................................... 35 
h. 
SAE/SADRs reporting (Investigator’s Responsibilities) ................................................................... 35 
i. 
Infusion Reactions ............................................................................................................................. 37 
Appendix 4: Package Insert ..................................................................................................................... 38 


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3. Background 
Coronavirus disease 2019 (COVID-19) progresses to respiratory complications as consequence of 
the exaggerated immune response of the host, producing a pro-inflammatory cytokine storm 
syndrome (i.e.: IL-6, TNF) and cytopenia, with a high mortality rate. 
 
Emergency treatments aiming to reduce individual cytokines (IL-6 and IL-1) specifically [or 
indirectly (JAK inhibitors and CCR5 antagonists) have shown survival benefit in patients with 
hyperinflammation, without increased adverse events. 
 
However, not being sufficient to reduce the rising mortality by COVID-19 other interventions to 
immunomodulate the life-threatening hyperinflammation are urgently needed. 
 
Therefore, the proposal for use of an anti-CD6 monoclonal antibody (Itolizumab) for the treatment 
of the COVID-19 cytokine storm syndrome complication. 
 
Why CD6? 
 
CD6 is constitutively expressed mainly on effector T cells (Teff) and hardly expressed on regulatory 
T cells (Tregs). CD6 stimulates the immune response and is overexpressed after lymphocyte 
activation. CD6 homes inflammatory cells to lesion, and its ligand ALCAM is upregulated after 
activation and in inflamed tissues. 
 
CD6 and viruses: 
 
CD6 is overexpressed on T-cells during chronic SIV infection, with impaired anti-viral responses, 
and is associated with SIV disease progression. HTLV-1 induces overexpression of ALCAM 
facilitating the trafficking of infected lymphocytes through the blood-brain barrier. ALCAM is 
increased on HIV+ monocytes and anti-ALCAM antibodies and the CCR2/CCR5 dual inhibitor 
reduce their transmigration. 
 
Why Itolizumab? 
 
Itolizumab is an anti-CD6 humanized IgG1 mAb. Itolizumab is an immune modulatory molecule. 
Itolizumab accumulates in the inflamed lesion. Itolizumab is used in Psoriasis and evaluated in other 
inflammatory diseases (Rheumatoid Arthritis) with a good safety profile as monotherapy or in 
combination with other drugs. Itolizumab has a legacy of therapeutic effect after discontinuation of 
the treatment period. Itolizumab has a potent anti-inflammatory effect reducing the production of 
pro-inflammatory cytokines IL-6, TNF, IFNγ, IL-17 and IL-1. 


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Hypothesis: 
 
Itolizumab in COVID-19 patients will control the pro-inflammatory cytokine storm syndrome, by 
immunomodulation of Teff function and trafficking to the inflammation site, sparing Tregs and 
preserving the anti-viral response, reducing the morbidity and mortality. 
Summary of Clinical Safety with Itolizumab: 
Itolizumab Injection has been administered to 338 patients with RA or psoriasis (including those 
with psoriatic arthritis) for up to 52 weeks in clinical trials till date and has been found to be well 
tolerated and safe. 
 
Itolizumab Injection (Alzumab™) was launched in India on 10 Aug 2013, as a solution for IV 
infusion of 1.6 mg/kg once every two weeks for 12 weeks, followed by 1.6 mg/kg every four weeks 
up to 24 weeks (each 5 mL vial contains 25 mg of itolizumab) for the treatment of patients with 
active moderate to severe chronic plaque psoriasis who are candidates for systemic therapy. 
 
Post-marketing, periodic safety update reports (PSURs) have been generated and submitted to the 
licensing authority. Based on these periodic reviews of safety data, the overall safety profile 
evaluation for Itolizumab Injection has remained unchanged. No new clinically significant issues 
arose which warranted changes to the current reference safety information (RSI). 
 
The most commonly (occurring in ≥5% patients) reported AEs in the Phase 3 study were infusion 
reactions (which are managed by premedication), pyrexia, upper respiratory tract infections and 
pruritus. The majority of the events were mild or moderate in severity. There were small transient 
reductions observed in the mean ALC during the initial infusions; however ALC increased with 
continued dosing. The small reduction in ALC did not appear to increase the incidence of infection. 
 
Summary of Contraindications/warning: 
ALZUMAB™ should not be administered to patients having history of severe allergy or known 
hypersensitivity reaction to any component of ALZUMAB™ or any murine proteins. Additionally, 
ALZUMAB™ is contraindicated in patients with any active serious infection including tuberculosis 
and HIV-AIDS. 
It is recommended that live/attenuated vaccines not be given concurrently with ALZUMAB™. 
As with other IgG antibodies, itolizumab may cross the placenta during pregnancy. The available 
clinical experience is too limited to exclude a risk, and administration of ALZUMAB™ is therefore 
not recommended during pregnancy. 


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Infections and Reactivation of Tuberculosis 
 
Physicians should exercise caution before and during Itolizumab Injection treatment in patients with 
a history of recurrent infections or underlying conditions which may predispose them to serious 
infections. Patients should be monitored closely for the development of signs and symptoms of 
infection during and after treatment with Itolizumab. 
 
4. Objectives 
 
Primary Objectives: 
 
To study the efficacy and safety of adding Itolizumab in patients with Moderate to Severe COVID- 
19 complications (Cytokine Release Syndrome). 
 
Secondary Objectives: 
 
To study the effect of immunomodulation by Itolizumab and its correlation to clinical improvement 
by evaluating biomarker data (IL6, TNF-a, IL17, IL1, Interferon -A etc.) before and after Itolizumab 
treatment 
 
5. Outcome Measures 
Primary Outcome Measures: 
1. Proportion of patients with deterioration of lung function as measured by*: 
• Stable SpO2 without increasing FiO2 
• Stable PaO2 without increasing FiO2 
2. Reduction of endo-tracheal intubation rate, measured as rate of patients needing intubation* 
3. Reduction in proportion of patients who need* 
• Non-invasive ventilation 
• Invasive mechanical ventilation 
• High flow nasal oxygen 
4. Time of duration of mechanical ventilation or time to end of mechanical, measured as 
elapsed time from the start date of mechanical ventilation to the weaning date, for patients 
needing intubation* 
5. One-month mortality rate between the two arms* [ Time Frame: up to 1 month ] 
 
1-month mortality is defined as the ratio of patients who will live after 1month from study 
start out of those registered at baseline 


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6. Change in inflammatory markers like CRP (C-reactive protein) level, d-Dimer, ferritin etc. 
[ Time Frame: Arm A; baseline, during treatment (Before every dose and 12 to 24 h after 
every dose) up to 1 month, Arm B: baseline, 12 to 24 h and approx. 7 and 14 days after 
randomization ] 
 
Secondary Outcome Measures: 
1. Biomarkers (IL-6, TNF-a, IL1, IL17, etc…) [ Time Frame: Arm A; baseline, during 
treatment (Before every dose and 12 to 24 h post dose) up to 1 month, Arm B; baseline, 12 
to 24 h and approx. 7 and 14 days after randomization ] 
 
2. Lymphocyte count [ Time Frame: Arm A; baseline and before every dose up to 1 month, 
Arm B; baseline, approx. 7 and 14 days after randomization ] 
Lymphocyte count assessed by routinely used determination of blood count 
 
3. PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F 
ratio) [ Time Frame: Arm A; baseline, during treatment (Before every dose and 48 h post 
dose) up to 1 month, Arm B: baseline, 48 h and approx. 7 and 14 days after randomization ] 
calculated from arterial blood gas analyses (values from 300 to 100) 
 
4. Number of participants with treatment-related side effects as assessed by Common 
Terminology Criteria for Adverse Event (CTCAE) version 5.0 [ Time Frame: during 
treatment and up to 30 days after the last treatment dose ]* 
graded according to CTCAE citeria (v5.0) 
 
5. Radiological response [ Time Frame: at baseline, after seven days and if clinically indicated 
(up to 1 month) ]* 
Thoracic CT scan or Chest XR 
 
6. Duration of hospitalization [ Time Frame: from baseline up to patient's discharge (up to 1 
month) ]* 
Days of hospitalization and ICU 
 
7. Remission of respiratory symptoms [ Time Frame: up to 1 month ]* 
time to independence from non-invasive mechanical ventilation calculated in days 
 
8. Remission of respiratory symptoms [ Time Frame: up to 1 month ]* 
time to independence from oxygen therapy in days 
 
* Applicable for both arms 


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6. Population 
Patients who have tested positive for virological diagnosis of SARS-CoV2 infection (PCR) are 
planned to be randomised for enrolment from various centres in India. 
 
Inclusion Criteria: 
1. Male or female adults above 18 years (not tested in children yet) 
2. Informed consent for participation in the study 
3. Confirmed virological diagnosis of SARS-CoV2 infection (RT-PCR) 
4. Hospitalized due to clinical worsening of COVID-19 infection 
5. Oxygen saturation at rest in ambient air ≤94% 
6. Patients who are in moderate to severe ARDS as defined by PaO2/Fio2 ratio of < 200 or 
more than 25% deterioration from the immediate previous value. 
7. Baseline serum ferritin level ≥ 400 ng/mL or IL-6 levels greater than 4 times ULN, if known 
 
Note: Either of Inclusion number 6 or 7 is required for inclusion of the patient into the study. 
Since there is logistical delay in getting results in time, biomarker data as inclusion criteria may 
be used if already known. 
Exclusion Criteria: 
1. Known severe allergic reactions to monoclonal antibodies 
2. Active tuberculosis (TB) infection 
3. History of inadequately treated tuberculosis or latent tuberculosis 
Note:. Latent tuberculosis should be excluded based on history, physical examination and 
chest x ray before dosing (day 1). QuantiFERON TB also should be performed, however 
considering criticality of patient condition, patient can be dosed without QuantiFERON TB 
test results. If QuantiFERON TB test is positive, then continuation of patient in the study is 
investigator’s discretion considering benefit-risk evaluation with the sponsor. 
4. In the opinion of the investigator, progression to death is highly probable, irrespective of 
the provision of treatments 
5. Patient on invasive mechanical ventilator support. 
6. Have received oral anti-rejection or immune-suppressive drugs within the past 6 months 
Note: Patient receiving oral anti-rejection or immune-suppressive drugs regularly in the last 
6 months will be excluded. Patient will be included if received short course of steroids. 
7. Participating in other drug clinical trials like using anti-IL-6 therapy like tocilizumab 
(participation in COVID-19 anti-viral trials may be permitted if approved by Sponsor) 
8. Patient on treatment of anti-IL-6 or plasma therapy as a part of supportive care 


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9. Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination 
10. Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study 
11. Patients with known history of Hepatitis B, Hepatitis C or HIV 
12. Absolute Neutrophils count (ANC) <1000 / mm3 
13. Platelet count <50,000 / mm3 
14. Absolute Lymphocyte count (ALC): <500/mm3 
Note: ANC, ALC and platelet counts can be done in local lab in the hospital. 
 
Planned number of subjects: 
Approximately 30 patients are considered sufficient to explore the study objectives and will be 
included in this study (number of patients may be increased if there is benefit observed in initial 
cohort of patients. There is no formal sample size calculation estimated). 
Method of assigning patient to treatment group: 
All eligible patients entering into the study will be randomized in 2:1 ratio to receive the treatment 
A/ B respectively. A computer derived randomization schedule is planned to be generated using 
appropriate system e.g. SAS to assign patient to treatment groups. Randomization will be central and 
appropriate system (e.g. remote telephone based, computer-based email, sealed envelope) will be 
used to distribute randomization schedule to the site 
Note: If the patient is randomised to Arm A and is not initiated itolizumab or not administer one full 
infusion, is then not considered randomized. The same randomisation code will be used for the 
subsequent subject in that particular site. 
 
Approximate number of sites: 
1-10 sites 
 
7. Treatment 
 
Treatment Intervention and Dose: 
 
Arm A: Best supportive care + Itolizumab 
 
The best supportive care to be given as per the institutions protocol will be administered 
 
(e.g: antivirals /antibiotics/ hydroxychloroquine; oxygen therapy, etc) + Itolizumab 


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Itolizumab 
Note: Premedication: Hydrocortisone 100 mg i.v (or equivalent short acting glucocorticoid) 
and Pheniramine 30 mg per i.v. about 30 ± 10 minutes prior to infusion. 
 
Start at 1.6 mg/kg dose iv infusion, if well tolerated, investigator has the discretion to continue with 
1.6 mg/kg dose every 2 weeks or 0.8 mg/kg weekly regimen. 
Subsequent dose and frequency can be modified, deferred or stopped if patient recovers as per 
investigator’s discretion. If patients’ overall parameters improve (if performed and RT-PCR is 
negative) further dose need not be given. Total infusion received during study duration can vary from 
1 to 4 for each patient. 
 
Arm B: Best supportive care 
 
The best supportive care to be given as per the institutions protocol will be administered 
 
(e.g: antivirals/antibiotics/ hydroxychloroquine; oxygen therapy, etc ) 
 
Dosing, Handling and Storage of Itolizumab 
• Itolizumab is to be stored in 6R, USP type-1, 10 mL glass vials, refrigerated condition at 
2°C to 8°C and is stable at that temperature for 36 months. 
• Itolizumab is intended for use under the guidance and supervision of a physician. The 
diluted infusion solution should be prepared by a trained medical professional using aseptic 
technique; as follows: 
• Calculate the dose and number of itolizumab vials needed. Itolizumab is provided as 
preservative-free single-use vial for IV infusion. Each vial contains 25 mg of itolizumab (5 
mg/mL) in a sterile, clear, colourless, preservative-free buffer 
 
• Itolizumab should be administered via IV infusion in 250 mL of 0.9% Sodium Chloride 
solution (normal saline). For this, dilute the appropriate dose of itolizumab to 250 mL with 
sterile normal saline. Gently mix. The total volume of the infusion will be more than 250 ml 
due to addition of the drug solution to 250 mL of 0.9% Sodium Chloride solution. 
 
• Fully diluted itolizumab solution should be allowed to reach room temperature prior to 
infusion. Before use, the fully diluted itolizumab solution may be stored at room 
temperature or refrigerated at 2-8ºC (36ºF-46ºF) protected from light. Itolizumab is stable in 
an infusion bag containing 250 mL of normal saline for up to 10 hours at room temperature. 
Do not administer as IV push or bolus. 
 
• The infusion must be administered over a period of not less than 120 minutes and using an 
infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size of 


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1.2 μm or less). Approximately 50 mL of diluted itolizumab solution should be 
administered during the first hour, followed by remaining solution (more than 
approximately 200 mL) in the next hour. The infusion period can be extended up to 8 hours 
for medical reasons. 
 
• The vials do not contain antibacterial preservatives. Therefore, any unused portion of the 
solution should not be stored for reuse. 
 
Study Drug Discontinuation: 
The investigator may decide to terminate the participation and discontinue further study 
participation of any patient. The recommended withdrawal criteria and dosing interruption criteria 
are presented below: 
1. Protocol violation: If a protocol violation occurs that in the clinical judgment of the 
investigator and/or after discussion with the sponsor may invalidate the trial, the patient will 
be withdrawn by the investigator. 
2. Consent is withdrawn: Patients have the right to withdraw from the trial at any time for any 
reason. 
3. Serious, life-threatening, or intolerable AEs or laboratory abnormalities in the investigator’s 
opinion, requires withdrawal from the study for safety reasons. 
4. Need arises to treat the patient with any medication that is not allowed as concomitant 
medication during the study; use of which, in the opinion of the investigator and/or medical 
monitor invalidates the study results or compromises the patient safety if continued on the 
study drug. 
5. The investigator also withdraws a patient if the sponsor terminates the study. 


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8. Assessments 
8.1 Schedule of Study Visits and Procedures 
 
Visit 
S1 
W1 
W2 
W3 
W4 
End of 
Study 
Weeks 
-2 to 0 
0 
1 
2 
3 
4th week 
Days 
-14 
1^ 
8^ 
15^ 
22^ 
30# 
Event 
Informed Consent 
X 
Medical History 
X 
Inclusion/Exclusion 
Criteriaa 
X 
Weight 
X 
X 
X 
X 
X 
X 
Physical 
Examination, Vital 
signs$ 
X 
X 
X 
X 
X 
X 
Hematology*;$ 
X 
X 
X 
X 
X 
X 
Biochemistry**;$ 
X 
X 
X 
X 
X 
X 
Chest X Ray/CT 
scan ## 
X 
X 
X 
X 
X 
Randomisation 
X 
Best Supportive 
Care 
X 
X 
X 
X 
Pre-medication @ in 
Arm A 
X 
X 
X 
X 
ALZUMAb infusion 
b 
X 
X 
X 
X 
Cytokines and 
Immunophenotyping 
assessment 
X 
Xd 
PaO2/FiO2 ratio 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
Daily Morning 
SOFA Scorec 
X 
X 
X 
X 
X 
Concomitant 
medication check 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
 
^ Window period: ± 48 Hours. 
a All inclusion / Exclusion criteria to be reviewed prior to first dosing. Screening period is up to 
14 days however screening and baseline visit can happen in one day and screening assessment 
can be considered as baseline assessments. 
b 1.6 mg/kg dose iv infusion, if well tolerated and improvement in patient observed, investigator 
has the discretion to continue with 1.6 mg/kg dose every 2 weeks or 0.8 mg/kg weekly regimen 
in combination therapy with standard of care (anti-viral and antibiotic drugs). Subsequent dose 
and frequency can be modified, deferred or stopped if patient recovers as per investigator’s 


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discretion. If patients’ overall parameters improve (if performed and RT-PCR is negative) further 
dose need not be given. Total infusion received during study duration can vary from 1 to 4 for 
each patient. If patient recovers/is discharged earlier than 30 days, then patient should be 
contacted telephonically to get status of the patient on 30th day after enrolment. 
c: Daily SOFA Scoring until patient moved out of ICU/equivalent, and later SOFA score 
frequency as per investigator discretion. If patient is not admitted in the ICU/equivalent at the 
time of enrolment, then it is recommended to capture these assessments daily for first 7 days. 
# Window period for assessment at 4th week or 30th day is ± 3 days. 
*Hematology assessments (blood test) include: hemoglobin, total leukocyte count, differential 
count, absolute neutrophil count, absolute lymphocyte count, and platelet count. 
**Biochemistry assessments (blood test) include blood urea, liver function tests (i.e. serum 
bilirubin, AST, ALT, ALP, Serum albumin), Lipid profile (including triglyceride), LDH, serum 
creatinine, Procalcitonin, d-Dimer, Trop-I, Ferritin. All blood samples for hematology and 
biochemistry must be collected prior to dosing, and additional as per investigator discretion. 
Note: Hematology and Biochemistry including (Procalcitonin, d-Dimer, Trop-I, Ferritin, LDH 
and CRP) are recommended every 48 to 72 hours. 
$: To be recorded daily: TLC; DLC, ANC, ALC; Platelet count; S. creatinine; T. Bilirubin; 
morning Vitals –pulse, BP, RR; Temperature (highest temperature of the day), PaO2/FiO2, MAP, 
GCS. These daily assessments are mandatory until patient moved out of ICU/equivalent. If 
patient is not admitted in the ICU/equivalent at the time of enrolment, then it is recommended to 
capture these assessments daily for first 7 days. 
@ Premedication: In arm A: Hydrocortisone 100 mg i.v (or equivalent short acting 
glucocorticoid) and Pheniramine 30 mg per i.v. about 30 ± 10 minutes prior to infusion. 
## To be repeated as suggested by the investigator in ICU setting. Earlier chest X ray report may 
be considered after discussing with sponsor. 
d: Cytokine levels in serum: such as IFN- α, TNF-α, IL-17, IL-6, IL-1, IL-4, IL-2, IL-10, GM- 
CSF, IFN-γ at baseline, before every dose and 12-24 h after dose in Arm A. In Arm B, same 
panel will be assessed at baseline, 12 to 24 h and approx. 7 and 14 days after randomization. 
Immunophenotyping in whole blood samples: Teff cells (CD4, CD8,Treg cells), TH17 and 
macrophage activated cells will be analysed at baseline, 12-24 h after 1st dose and 24h after 
the second/last dose in Arm A and at baseline, 12-24 h and approx. 7 days after randomization 
in Arm B. 


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Timing of administration of Itolizumab: 
Patients should be randomized in the trial and given Itolizumab who are in moderate to severe ARDS 
as defined by PaO2/Fio2 ratio of < 200 or more than 25% deterioration from the immediate previous 
value. 
OR 
 
Baseline serum ferritin level ≥ 400 ng/mL or IL-6 levels greater than 4 times ULN, if known 
Note: Either of Inclusion number 6 or 7 is required for inclusion of the patient into the study. Since 
there is logistical delay in getting results in time, biomarker data as inclusion criteria may be used if 
already known. 
8.2 Laboratory Procedures 
 
Collection of Biomarker Samples: 
 
Cytokine levels in serum: such as IFN- α, TNF-α, IL-17, IL-6, IL-1, IL-4, IL-2, IL-10, GM-CSF at 
baseline, weekly before every dose and 12-24 h after dose in Arm A. In Arm B, same panel will be 
assessed at baseline, 12 to 24 h and approx. 7 and 14 days after randomization. 
Immunophenotyping in whole blood samples: Teff cells (CD4, CD8,Treg cells), TH17 and 
macrophage activated cells will be analysed at baseline, 12-24 h after 1st dose and 24h after the 
second/last dose in Arm A and at baseline, 12-24 h and approx. 7 days after randomization in Arm 
B. 
 
Blood sample collections and handling instructions: 
 
Two sets of sample collection are required: 
1) Serum Sample 
Samples to be collected: Blood 4-5 ml; (approx. 2-2.5 ml serum can be collected from blood) 
Time points: Refer to section 8.1: Schedule of Study Visits and Procedures 
Storage of sample: Serum separation will be performed at the Site/Clinic. 
 
For each visit, serum samples should be immediately aliquoted into 2 vials of approx.1 ml each and 
then stored at -70o C ± 15°C or dry ice. Transportation should take place in dry ice only. Once at 
CRO the samples should be stored frozen at -80oC till used for batch analysis. This samples will be 
used for cytokines/chemokines. 
Note: if -20 freezers are only available, then samples to be shipped within 24h in -80 oC. 


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To be performed at: 
 
Syngene International Ltd. 
Tower I, Semicon Park, Phase-II, 
Hosur Road, Bangalore 560 100, 
Karnataka, India 
 
2) Whole blood Collection: 
 
Additionally, approximately 4ml of blood is to be drawn for immunophenotyping. . Sample should 
be stored at 2-8 oC. NOT FROZEN and shipped to Syngene international Ltd or analysed locally. 
The sample has to be shipped and should reach Syngene or local lab for analysis within 48 h. 
Time points: Refer to section 8.1: Schedule of Study Visits and Procedures 
Specific details will be included in the Laboratory manual/instruction document sent to the sites. 
 
9. Safety Monitoring 
 
Adverse Events and Safety Reporting 
For the evaluation of safety, all the evidences of adverse events occurring during the study will be 
considered. The clinical laboratory tests will be conducted at local labs as and when necessary for 
safety evaluation. Any investigation, at any time during the study may be conducted at the local lab 
as per investigator’s discretion, in order to monitor safety. Definitions of adverse events and safety 
reporting for SAEs and SUSARs will be as per regulatory requirements for marketed products (Refer 
Appendix 3 for details on definitions and reporting that Investigators must follow to satisfy 
regulatory requirements and ensure patient safety and well-being). 
Special Precautions 
In general, according to previous data, ALZUMAbTM is safe and well tolerated. However, it is 
recommended that investigators should exercise caution before administering ALZUMAbTM in 
subjects with a history of recurrent infections, or underlying conditions which may predispose them 
to infections. Subjects who develop a new infection while undergoing treatment with ALZUMAbTM 
should be monitored closely and treated according to standard treatment guidelines. While previous 
clinical study data has not revealed the incidence of opportunistic infections, it is recommended that 
Investigators be watchful for occurrence of tuberculosis and opportunistic infections like 
candidiasis. Administration of ALZUMAbTM should be discontinued if a subject develops a serious 
infection (other than COVID19). In case a reactivation of latent tuberculosis occurs in study subjects 
during the clinical study, immediate treatment in accordance with standard medical practice should 
be instituted and the subjects should be withdrawn from the study. 


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10. Data Handling Procedures 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical study necessary for the reconstruction and evaluation of the study. Source data are 
contained in source documents. Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subject`s diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical study. 
Location of Data 
All records and documents pertaining to the study will be maintained in the permanent files of the 
Investigator and will be available for inspection by the authorized party at any time. 
Statistical Analysis 
In general, continuous variables is summarized using descriptive statistics such as mean, standard 
deviation, 95% confidence interval (CI), minimum, and maximum. Categorical variables are 
summarized using proportions (counts and percentages). All statistical tests will be performed at 5% 
level of significance (two-sided test) and p-value<0.05 considered statistically significant (if 
necessary). All statistical analysis will be performed using SAS® (version 9.4 or higher) system 
software (SAS Institute Inc., USA)/or R/or EAST/or NCSS software. 
 
11. Administrative Procedures 
Ethics and Good Clinical Practice 
This research will be carried out in accordance with the clinical research guidelines established by 
the basic principles defined in the revised New Drugs and Clinical Trials 2019, India and the 
principles enunciated in the Declaration of Helsinki [Ethical Principles for Medical Research 
Involving Human Subjects, revised, October 2013]. The investigator is responsible for overall 
activities at the center in accordance with Indian ICH-GCP guidelines, current New Drugs and 
Clinical Trials 2019 and ethical guidelines for biomedical research on human subjects issued by 
ICMR. 
Interim study report - Data will be provided to DSMB (constituted prior to first patient screened) on 
a periodic basis. Based on DSMB recommendation, interim clinical study report may be prepared 
and submitted to DCGI/regulatory agencies. 
Subject confidentiality - All reports, CRF and communications relating to subjects in the study will 
identify each subject only by the subject number, and the protocol number. 


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Publication of Results 
Any formal presentation or publication of data from this trial will be considered jointly between the 
investigator and the sponsor, as indicated in the contract agreement undersigned by both parties. 


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References 
 
i. 10.1016/j.jaad.2014.01.897. Epub 2014 Apr 2. PubMed PMID: 24703722. 
https://externalmediasite.partners.org/Mediasite/Play/45a9a74f18ec45deb338e00ac4cf4e281d?fb 
clid=IwAR1HfhdrW_SqchU91OPAL0lUKbM5Mdlt90oz81oBs2RyViigO9-tOq8HK0w 
 
ii. Mehta P, et al. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet. 2020 Mar 16. pii: S0140-6736(20)30628-0. 
 
iii. Richardson P, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. 
Lancet 2020; 395: e30–31. 
 
iv. Shakoory B, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis 
patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial. 
Crit Care Med 2016; 44: 275–81. 
 
v. Chinese Clinical Trial Registry. A multicenter, randomized controlled trial for the efficacy and 
safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). Feb 13, 2020. 
http://www.chictr.org.cn/ showprojen.aspx?proj=49409. 
 
vi. https://www.cytodyn.com/newsroom/press-releases/detail/395/cytodyn-files-modified-ind-and- 
protocol-for-phase-2 
 
vii. Enyindah-Asonye G, et al. Overexpression of CD6 and PD-1 Identifies Dysfunctional CD8(+) T- 
Cells During Chronic SIV Infection of Rhesus Macaques. Front Immunol. 2020 Jan 8;10:3005. 
 
viii. Curis C, et al. Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated 
Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes 
through the Blood-Brain Barrier. J Virol. 2016 Jul 27;90(16):7303-7312. 
 
ix. Rodríguez PC, Prada DM, Moreno E, Aira LE, Molinero C, López AM, Gómez JA, Hernández 
IM, Martínez JP, Reyes Y, Milera JM, Hernández MV, Torres R, Avila Y, Barrese Y, Viada C, 
Montero E, Hernández P. The anti-CD6 antibody Itolizumab provides clinical benefit without 
lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical 
trial. Clin Exp Immunol. 2018 Feb;191(2):229-239. 


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x. Bughani U, Saha A, Kuriakose A, Nair R, Sadashivarao RB, Venkataraman R, Patel S, 
Deshchougule AT, S SK, Montero E, Pai HV, Palanivelu DV, Melarkode R, Nair P. T cell 
activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab. PLoS One. 
2017 Jul 3;12(7):e0180088. 
 
xi. Chopra A, Chandrashekara S, Iyer R, Rajasekhar L, Shetty N, Veeravalli SM, Ghosh A, 
Merchant M, Oak J, Londhey V, Barve A, Ramakrishnan MS, Montero E. Itolizumab in 
combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a 
phase 2, randomized, open-label, parallel-group, dose-ranging study. Clin Rheumatol. 2016 
Apr;35(4):1059-64. 
 
xii. Dogra S, D S K, Budamakuntla L, Srinivas CR, Khopkar U, Gupta S, Shetty N, Pratap DV, 
Gopal MG, Rao TN, Garg V, Sumathy TK, Saraswat A, Bhat R, Kura M, Pandey N, Shah R, Sai 
Krishna K, Padmaja D, Manmohan G, M S R, Barve A, Montero E. Long-term efficacy and 
safety of itolizumab in patients with moderate-to-severe chronic plaque psoriasis: A double-blind, 
randomized-withdrawal, placebo-controlled study. J Am Acad Dermatol. 2015 Aug;73(2):331- 
3.e1. 
 
xiii. Nair P, Melarkode R, Rajkumar D, Montero E. CD6 synergistic co-stimulation promoting 
proinflammatory response is modulated without interfering with the activated leucocyte cell 
adhesion molecule interaction. Clin Exp Immunol. 2010 Oct;162(1):116-30. 
 
xiv. Lalueza A, Ayuso B, Arrieta E et al. Elevation of serum ferritin levels for predicting a poor 
outcome in hospitalized patients with influenza infection. Clin Microbiol Infect. (2020) [Epub 
ahead of print]. 


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12. Appendices 
Appendix 1: World Medical Association Declaration of Helsinki-Ethical 
Principles for Medical Research on Human Patients 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 


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Preamble 
 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles. 
 
General Principles 
 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics declares 
that, “A physician shall act in the patient's best interest when providing medical care.” 
 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
 
5. 
Medical progress is based on research that ultimately must include studies involving human 
subjects. 
 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest with 
the physician or other health care professionals and never with the research subjects, even though 
they have given consent. 


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10. 
Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
11. 
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
 
12. 
Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
 
13. 
Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
 
14. 
Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research subjects. 
 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  
 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
 
17. 
All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study. 


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Vulnerable Groups and Individuals 
 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non- 
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
 
Scientific Requirements and Research Protocols 
 
21. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee must 
be transparent in its functioning, must be independent of the researcher, the sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or eliminate 
any of the protections for research subjects set forth in this Declaration. 
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 


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Privacy and Confidentiality  
 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
 
Informed Consent  
 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a research 
study unless he or she freely agrees. 
 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non- 
written consent must be formally documented and witnessed. 
 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. 
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
 
28. 
For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead be 
performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
 
29. 
When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that assent 
in addition to the consent of the legally authorised representative. The potential subject’s dissent 
should be respected. 


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30. 
Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
 
31. 
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship. 
 
32. 
For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
 
Use of Placebo 
 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive any 
intervention less effective than the best proven one, placebo, or no intervention will not be subject 
to additional risks of serious or irreversible harm as a result of not receiving the best proven 
intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
 
Research Registration and Publication and Dissemination of Results 


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35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37. 
In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 


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Appendix 2: Informed Consent Form 
 
 
Please see informed consent form. 


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Appendix 3: Adverse Event Definitions and Safety Reporting for Investigators 
(as per requirements for marketed products) 
a. Definitions 
An Adverse Event/Experience [AE] is any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavourable and unintended sign [including an abnormal laboratory 
finding, for example], symptom, or disease temporally associated with the use of a medical product, 
whether or not considered related to the medical product. 
An Adverse Drug Reaction [ADR] is defined as any untoward and unintended responses to an 
investigational medicinal product related to any dose administered 
In accordance with the above definition, adverse events may include: 
• Worsening [change in nature, severity or frequency] of conditions present at the onset 
of the study 
• Condition detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study 
An AE does not include: 
• Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, 
transfusion), the condition that leads to the procedure is an adverse event. 
• Pre-existing diseases or conditions present or detected prior to start of the study drug 
administration that does not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g. 
hospitalization for elective surgery, social and / or convenience admissions). 
A Serious Adverse Event [SAE] is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening* 
• Results in persistent or significant disabling / incapacity 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization# 
• Occurrence of congenital anomaly or birth defect if relevant 
• Other important medically significant events that may not result in death, be 
immediately life threatening, or require hospitalization, may be considered an SAE 
when, based upon appropriate medical judgment, they may jeopardize the well-being 
of the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias, or 


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convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse. 
*The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
#“Inpatient hospitalization” does not imply that the subject must have had an overnight stay 
in the hospital. If the subject was admitted to the hospital for less than a day for the purpose 
of treatment or observation, the definition of “Inpatient hospitalization” is met, provided the 
subject is admitted solely for treatment of the event and not admitted for any social reasons, 
ease of compliance, day care procedures, or for medical or hospital records (insurance 
reimbursement) purpose. Although, brief treatment in an outpatient clinic or Emergency 
department 
does 
not 
constitute 
“inpatient 
hospitalization”, 
depending 
on 
the 
intervention/treatment required for the event, it may satisfy the criteria of inpatient 
hospitalization to be reported as an SAE. 
An Unexpected Adverse Drug Reaction is an adverse reaction, the nature or severity of which is 
not consistent with the applicable product information [e.g., Prescribing Information] 
Events previously unobserved or undocumented must be classified as unexpected on this basis, and 
not on the basis of what might be anticipated from the pharmacological properties of a medicinal 
product. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the 
AE/SAE and not the individual signs/symptoms. 
 
b. Classification of Adverse Events 
All adverse events will be classified, MedDRA coded (Version 17.0 or higher) and documented 
as per the grading system presented in NCI CTCAE v5.0. 
In the course of the study, if adverse events are not covered in the NCI CTCAE v5.0 occur the 
Investigator will determine the severity of these adverse events as follows: 
• Mild: Awareness of symptoms but easily tolerated 
• Moderate: Discomfort enough to cause interference with usual activity 
• Severe: Incapacitating with inability to work or carry out usual activity 
• Life threatening 
• Death related 
 
The SAE will not be closed out if it is of changing severity during the course. It will be reported 
with changes in the severity as it upgrades in follow up reports such that each upgraded sequelae will 
not be recorded as a new SAE but continuation of same SAE and the serious and unexpected adverse 


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reactions will be reported to DCGI within the stipulated timeline. Only the highest grade of severity 
will be considered for analysis purpose. 
c. Clarification in Reporting of Deaths 
All subject deaths (regardless of relationship to study drug) should be reported for subjects while on 
the study protocol. This should be recorded on the end of study CRF page and the SAE form. If a 
subject dies after signing consent but before the first dose of the study drug, this will also be recorded 
in the CRF. Death is an outcome of an adverse event and not an adverse event in itself. All reports 
of subject death should include an adverse event term (other than “Death”) for the cause of the death. 
If an adverse event term is not provided, the treating physician will be queried to obtain the cause of 
death. Only in the rare occurrence that no verbatim description of an adverse event can be obtained 
from the investigative site, will “Death-Unknown cause” be used as the event term. 
d. Causality of the adverse event: 
The Investigator’s causality assessment should consider the potential etiologies for the observed 
adverse event. An adverse event may be related to the study drug, other concomitant medications, 
the underlying disease pathology, inter-current illness, a procedure performed in the course of the 
study, or another reason. Among the potential etiologies, the investigator should make a 
determination based on the most likely causal relationship. When a causality assessment is provided 
for a SAE, it is important to include a rationale for the assessment so that a better understanding of 
the reported event can be compiled. The rationale should be accompanied by all available supporting 
evidence, including relevant laboratory tests, histopathology evaluations and the results of other 
diagnostic procedures. 
The Investigator will make a judgment considering whether or not, in his opinion, the adverse event 
was related to the drug according to the following classification. 
The likelihood of the relationship of the adverse event to the study drug is to be recorded as follows. 
Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration and which cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the drug [de-challenge] should be clinically 
plausible. The event must be definitive pharmacologically or as a logical phenomenon, using a 
satisfactory re-challenge procedure if necessary. 
Probable /Likely: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs 
or chemicals and which follows a clinically reasonable response on withdrawal [de-challenge]. Re- 
challenge information is not required to fulfill this information. 
Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug , but which could also be explained by concurrent disease or other drugs 
or chemicals. Information on drug withdrawal may be lacking or unclear. 


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Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to 
drug administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Unrelated: Event or laboratory test abnormality – is clearly NOT related to the investigational 
agent(s) 
e. Laboratory Abnormalities 
Abnormal laboratory findings (e.g., biochemistry, hematology) or other abnormal assessments (e.g., 
electrocardiogram, X-rays, vital signs) per se are not reported as AEs. However, abnormal findings 
that are deemed clinically significant must be recorded as AEs if they meet the definition of an 
adverse event (and recorded as an SAE if they meet the criteria of being serious) as described 
previously, as per the classifications accorded in NCI CTCAE v5.0 for laboratory AEs. 
Clinically significant abnormal laboratory or other abnormal findings that are detected after study 
drug administration or that are present at baseline and worsen following the administration of study 
drug are included as AEs (and SAEs if serious). The Investigator should exercise his or her medical 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. Usually, the abnormality should be associated with a clinically evident sign or 
symptom, or be likely to result in an evident sign or symptom in the near term, to be considered 
clinically significant. 
f. Documentation of Adverse Events 
Any AE occurrence during the study must be documented in the subject`s medical records in 
accordance with the Investigator`s normal clinical practice and on the AE page of the CRF. SAEs 
that occur during the study must be documented in the subject’s medical record, on the AE page of 
the CRF and on the SAE form of the CRF. 
The Investigator should attempt to establish a diagnosis of the event based on the signs, symptoms 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE (and 
SAE if serious) and not the individual signs/symptoms. If a clinically significant abnormal laboratory 
finding or other abnormal assessment meets the definition of an AE, then the AE page of the CRF 
page must be completed as appropriate. In addition, if the abnormal laboratory finding meets the 
criteria for being serious, the SAE form must also be completed. A diagnosis, or clinical signs or 
symptoms if the diagnosis is unknown, rather than the clinically significant laboratory finding or 
abnormal assessment, should be used to complete the AE/SAE page. As additional information 
becomes available and a diagnosis is achieved, the signs/symptoms or abnormal finding verbatim 
should be updated on the CRF. 
If no diagnosis is known and clinical signs or symptoms are not present, then the abnormal finding 
should be recorded on the AE/SAE page. If an SAE report is completed, pertinent laboratory data 
should be recorded on the SAE form, preferably with baseline values and copies of laboratory reports. 
The SAE form should be completed as thoroughly as  possible. It is very important  that the 


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Investigator provide an assessment of the causal relationship between the event and the study drug 
at the time of the initial report. 
g. Follow-up of Adverse Events and Serious Adverse Events 
Subjects will be monitored for adverse events/reactions to the study drug and/or study procedures 
during the study product administration. All AEs related to ALZUMAbTM and all SAEs must be 
followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject dies or is lost to follow-up. The investigator will administer appropriate treatment for the 
SAE resolution. The Investigator is responsible to ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature and/or causality 
of the AE/SAE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
h. SAE/SADRs reporting (Investigator’s Responsibilities) 
All study drug related SAEs (SADRs), occurring after the patient signs the informed consent and 
until the one year follow-up period is over or until the patient has prematurely stopped 
participation in the study must be reported to drug manufacturer (Biocon Ltd) within 24 hours of 
learning of its occurrence. 
Recurrent episodes, complications, or progression of the initial SADRs must be reported as follow- 
up to the original episode within 24 hours of the Investigator receiving the follow-up information. 
An SADR occurring at a different time interval should be reported separately as a new event. 
Information about all SADRs is collected and recorded on the Serious Adverse Event Report Form. 
The Investigator must assess the relationship to drug and report all SADRs by completing the SAE 
Report Form in English, and send the completed, signed form within 24 hours to Biocon Ltd. The 
original SAE Report Form and the fax confirmation sheet must be kept with the documentation at 
the site. The investigator should notify all SADRs to Biocon through email. The telephone and fax 
number of the contact persons listed below for SADRs reporting can be used as alternate modes of 
communication. 
The Investigator must inform one of the responsible persons of Biocon Ltd (Pharmacovigilance 
personnel listed below) by telephone as soon as possible and not later than 24 hours of the 
occurrence of an SADR. 
Questions pertaining to a specific serious adverse drug reaction occurring in a patient should be 
directed to the contact persons listed in the protocol. 
Follow-up information should be sent to Biocon Ltd PVD (where the original SAE Report Form was 
sent), using a new SAE Report Form stating that this is a follow-up to the previously reported SAE 
and giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event even if it occurs at a different time 
interval. The follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the patient continued or withdrew from surveillance 
participation. If there are SADR/SAEs, they should be intimated to all the other IRB/IEC through 
the sites. They should be intimated to the other sites within 14 calendar days of SAE/SADR 
occurrence and the sites will in turn inform the IRB/IEC within 24 hours of getting the information. 


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If the SAE/SADRs is not previously documented in Package Insert (unexpected, new occurrence) a 
Biocon PVD personnel or designee may urgently require further information from the Investigator 
for Health Authority reporting. All SAE/SADRs will be reported to DCGI, and relevant IRB/IEC by 
the Investigator within 24 hours (first intimation) and due analysis within 14 days of first awareness 
of the event in required format as per the New Drugs and Clinical Trials 2019. The same guiding 
principle as described above for initial and follow up reports of SAE/SADRs will be followed for 
SAE/SADRs reporting to DCGI and IRB/IEC. Any report of the SAE/SADRs, after due analysis 
shall be forwarded by the sponsor to the DCGI, IRB/IEC where the trial has been conducted, within 
fourteen days of knowledge of occurrence of the serious adverse event as specified in Table 5 (as per 
the timeline for marketed products in New Drugs and Clinical Trials 2019). 
All study drug related Serious Adverse Events should be reported by the Investigator to 
Biocon Pharmacovigilance department and email address given below: 
 
Pharmacovigilance Department 
Clinical Development & Medical affairs, 
Biocon Biologics India Limited, 
Biocon House, Semicon Park, 
Bangalore 560 100: India 
 
 
Email: DrugSafety@biocon.com 
Fax +91 80 6775 5323 
Toll Free No: 1800 102 9465 
 
It should be sent within 24 hours of the occurrence of the event. 
To ensure the patient safety each pregnancy in a patient occurring after the patient begins taking 
drug until the treatment is stopped should be reported to the above contact details of Biocon 
Pharmacovigilance within 24 hours of learning of its occurrence. The pregnancy should be followed 
to determine the outcome including the spontaneous or voluntary termination, details of birth, the 
presence of any birth defects, congenital abnormalities. Any patient in whom pregnancy occurs after 
signing of the informed consent form and before the patient is enrolled should be excluded from the 
surveillance. 
The cases of pregnancy reported by female patients or female partners of male patients will be 
followed up till the outcome. Investigator should fill the Pregnancy Reporting Form and send to the 
above mentioned personnel. Pregnancy follow up should be recorded in the same form and should 
include an assessment of the possible relationship to ALZUMAbTM of any pregnancy outcome. 
The Investigator should arrange for the appropriate counseling of patients to discuss the 
implications of continuing or terminating pregnancy. 
Pregnancies occurring during the post-treatment follow-up shall be reported and followed up if 
suspected to be unintended pregnancies related to ALZUMAbTM or are associated with abnormal 
outcome, birth defect or congenital anomaly related to ALZUMAbTM. 


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i. Infusion Reactions 
During administration of ALZUMAbTM some patients may develop infusion reactions. Infusion 
reactions are most likely to occur during the first cycle of dosing and tend to decrease in severity 
and frequency upon subsequent infusions. Acute infusion-related reactions are expected with 
Itolizumab administration. Symptoms may include nausea, flushing, urticaria, cough, 
hypersensitivity, pruritus, rash, wheezing, dyspnea, dizziness, headache, and hypertension. Acute 
infusion reactions should be treated using the standard of care; and physicians may need to delay 
dosing till the patient is stabilized. 
ii Overdose Treatment: 
Since the investigational products are directly administered by personnel involved in the study in 
controlled manner, overdose is unlikely to occur. However, in case of overdose, the management 
will be as per standard of care. In case there is overdose, the same should be informed to sponsor 
safety team on real time basis. Overdose with associated adverse events should be informed to 
sponsor safety team in line with AE/SAE reporting timelines (as applicable). 


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Appendix 4: Package Insert 
For the use of Registered Dermatologist and Specialist Medical Practitioner 
ALZUMAbTM 
Itolizumab Injection 
NAME OF THE MEDICINAL PRODUCT 
ALZUMAbTM 
COMPOSITION 
Each vial contains 25 mg of Itolizumab. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody. 
Each mL contains 5 mg of Itolizumab for intravenous use. For full list 
of excipients, see Pharmaceutical Particulars. PHARMACEUTICAL 
FORM 
Solution for intravenous infusion 
Colorless 
and 
transparent 
solution 
PHARMACOLOGICAL 
PROPERTIES 
Mechanism of Action 
Itolizumab is a humanized recombinant anti-CD6 mAb of immunoglobulin (Ig) G1 isotype that binds to domain 1 of 
CD6. The CD6 leukocyte differentiation antigen is a membrane glycoprotein mainly expressed on the surface of mature 
thymocytes, in most peripheral blood CD3+ T-cells and in a subtype of B-lymphocytes called B1a cells. In peripheral 
blood T-cells, CD6 participates in cell activation as a co-stimulatory molecule. The ligand of CD6, Activated 
Leukocyte-Cell Adhesion Molecule (ALCAM) is widely distributed in normal tissues, including the thymus, spleen, 
lymph nodes and skin. Itolizumab immunomodulates human lymphocytes without interfering with the binding of CD6 
to ALCAM. 
Preclinical studies with T-cells showed that the antibody blocks intracellular Mitogen Activated Protein Kinase 
(MAPK) and Signal Transducer and Activator of Transcription-3 (STAT-3) signaling pathways, the secretion of 
pro-inflammatory cytokines (including tumor necrosis factor-α, interferon-γ and interleukin-6) and T-cell 
proliferation, even when co-stimulated with ALCAM. 
Pharmacodynamic Properties 
A range of in vitro and in vivo pharmacology studies demonstrated that Itolizumab reacts with human CD6, and is 
therapeutically effective in the severe combined immunodeficiency disease- human (SCID-Hu) xenograft model of 
psoriasis in mice. In a cross-reactivity study with normal adult human tissues, Itolizumab specifically recognized T- 
cells, but did not show any cross- reactivity to other cells or tissues. In another study, Itolizumab was found to have 
similar reactivity to CD6-expressing cell lines as a commercial anti-CD6 monoclonal antibody. 
Clinical studies 
The efficacy and safety of ALZUMAbTM were assessed in 2 randomized, multicentric studies in patients 18 years of 
age and older with chronic, stable plaque psoriasis involving ≥10% body surface area, a minimum Psoriasis Area and 
Severity Index (PASI) score of ≥10. All patients had 
either failed or were intolerant to or had a contraindication to at least one prior systemic anti- psoriatic therapy. 


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The claim of efficacy is supported primarily by data from pivotal phase 3 trial (TREAT-PLAQ; Study II) in moderate 
to severe plaque psoriasis. Supporting efficacy data from this patient population was also collected from the phase 
2 trial (Study I). 
Study I (Study T1hAb-CT1-001-07) was a 32-week, randomized, single-blind, parallel, phase 2 study to evaluate the 
efficacy and safety of Itolizumab in 40 patients. Patients were randomized into 8 groups (5 patients per group), who 
received 0.4 or 0.8 mg/kg (once every week, once in 2 weeks, or once in 4 weeks); or 1.6 mg/kg (once in 2 weeks or 
once in 4 weeks). Patients were treated for 8 weeks and were followed up for 24 weeks. Efficacy parameters of the 
study included PASI, Investigator’s Global Assessment (PGA), Psoriasis Severity Scale (PSS); the Short Form-36 
(SF-36), Dermatology Life Quality Index (DLQI) questionnaires to assess changes in patient quality of life; and 
reductions in epidermal as well as rete thickness. 
In the overall study cohort (n=40), the mean PASI score decreased consistently for all patients from baseline visit to 
Week 12. The mean PASI score at baseline was 22.32±8.84 which was significantly reduced to 7.62±7.80 at Week 8 
and 6.23±7.14 at the end of Week 12 (p<0.0001). Overall, 72.5% of patients achieved PASI 50 and, 45% achieved 
PASI 75 at Week 12. The reduction in mean PASI scores observed at the end of treatment phase (Week 8) continued 
to persist till the end of Week 12 in all dosing cohorts, 62.16% of patients improved or maintained their PASI 
improvement achieved at Week 8 till Week 12 after stopping the study drug. The PGA and PSS scores reduced 
consistently from baseline to Week 12 (p<0.0001) for all groups in the study. Moreover, 65% of the patients achieved 
a score of “minimal” or “clear” by PGA scoring criteria. The proportion of patients with improvement in PASI and 
PGA scores at Weeks 8 and 12 is shown in Table 1. In addition, DLQI and SF-36 assessment suggested improvement 
in the quality of life in the patients owing to improvement of their skin lesions. Lastly, there were significant reduction 
in mean epidermal (p=0.0005) and rete thickness (p<0.0001) at Week 12 compared to baseline; with maximal 
reduction in both epidermal and rete thickness seen at Week 8. 
Table 1. Summary of Itolizumab Efficacy Data in Phase 2 Study: Proportion of Patients 
Achieving Improvement in PASI and PGA Scores, at Week 8 and 12. 
Response achieved at: 
Proportion of patients achieving PASI and PGA response [n/N (%)] 
PASI 50 
PASI 75 
PASI 90 
PASI 100 
PGA score 
(“clear” or “minimal”) 
Week 8 
(N=40) 
27/40 
(67.50%) 
17/40 
(42.50%) 
8/40 
(20%) 
3/40 
(7.50%) 
24/40 
(60%) 
Week 12 
(N=40) 
29/40 
(72.50%) 
18/40 
(45%) 
12/40 
(30%) 
3/40 
(7.50%) 
26/40 
(65%) 
PASI: psoriasis area and severity index; PGA: Investigator’s global assessment 
n=number of patients with response; N=total number of patients 
Study II (“TREAT-PLAQ”; Study T1hAb-CT3-002-09) was a 52-week, randomized, double- blind, placebo- 
controlled, one-way cross over, pivotal phase 3 study to assess the efficacy and safety of Itolizumab. 
The study was conducted in three double blind phases post screening (2 weeks) and washout phases (if necessary, 
up to 8 weeks depending on current treatment): 
Placebo controlled phase (12 weeks), 
Crossover of Placebo and consolidation treatment phase (16 weeks) and, Randomized 
withdrawal phase (24 weeks). 
In this study, 225 patients were treated as follows: 


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Week 1-12 (double-blind, placebo-controlled): Patients were randomized in a 2:2:1 ratio to following treatment 
arms: (A) Itolizumab 0.4 mg/kg every week for 4 weeks, followed by 
1.6 mg/kg every 2 weeks for 8 weeks; (B) Itolizumab 1.6 mg/kg every 2 weeks for 12 weeks; or 
(C) placebo for 12 weeks. 
Week 12-24 (double-blind): Patients from arms A and B continued to receive Itolizumab at the dose of 1.6 mg/kg 
every 4 weeks till week 24; and patients from arm C received Itolizumab at 
1.6 mg/kg every 2 weeks till Week 24. 
Week 24-52: Week 24-28 was a treatment-free period. 
Patients from arm C received Itolizumab at the dose of 1.6 mg/kg every 12 weeks, and patients from arm A and B 
were re-randomized based on their PASI response: 
Patients who achieved ≥PASI 75 were randomized (1:1) to receive either itolizumab 1.6 mg/kg every 12 weeks or 
placebo (double-blind) till Week 52; 
Patients who achieved ≥PASI 50 but <PASI 75 response received itolizumab 0.4 mg/kg every week for 4 weeks 
followed by 1.6 mg/kg every 4 weeks (open-label); 
Patients failing to achieve PASI 50 were withdrawn from the study. 
The last dosing visit (at Week 48) was followed by a 4-week treatment-free follow-up period. In the TREAT- 
PLAQ study, the primary endpoint was the proportion of patients achieving 
≥PASI 75 at Week 12 in each itolizumab cohort as compared to placebo. Other evaluated outcomes measured at 
different intervals were, (a) proportion of patients achieving PASI 50, 75, 
90 and 100 from baseline in each itolizumab cohort; (b) proportion of patients with PGA score “clear” or “minimal” 
and, (c) change in health-related quality of life as assessed by SF-36 and DLQI. 
Two hundred and twenty patients were included in the efficacy population (full analysis set - intent-to-treat [FAS- 
ITT] population). The proportions of patients who achieved PASI 50, 75, 90 and 100 scores at Week 12, 28 and 52 
are displayed in. Table 2. In the primary analysis, at Week 12 both itolizumab treatment arms A and B demonstrated 
significant efficacy over arm C (placebo from Weeks 1-12): 27% of patients from arm A, 36.4% from arm B and 
2.3% from arm C achieved PASI 75 at Week 12. The proportion of PASI 50 responders followed the same trend as 
for PASI 
75. Thus, itolizumab produced improvements in PASI 50 and PASI 75, both clinically meaningful 
outcomes for psoriasis patients. 
Table 2. Summary of Itolizumab Efficacy Data in the TREAT-PLAQ Study: Proportion of 
Psoriasis Patients Achieving PASI 50, 75, 90 and 100 at Week 12, 28 and 52. 
Response 
achieved at: 
Treatment 
arm 
Proportion of patients achieving PASI response [n/N (%)] 
PASI 50 
PASI 75 
PASI 90 
PASI 100 
Week 
12 
(N=220 
A 
52/89 (58.4%) 
24/89 (27.0%) 
10/89 (11.2%) 
2/89 (2.2%) 
B 
59/88 (67.0%) 
32/88 (36.4%) 
15/88 (17.0%) 
3/88 (3.4%) 
C (placebo) 
10/43 (23.3%) 
1/43 (2.3%) 
0/43 
0/43 
p values 
0.0003 (A vs. C):
<0.0001 (B vs. 
C): 0.2160 (A 
0.0172 (A vs. C):
0.0043 (B vs. C) 
0.0234 (A vs. C):
0.0046 (B vs. C):
0.2477 (A vs. B) 
 
- 
Week 
28 
A 
70/89 (78.7%) 
41/89 (46.1%) 
17/89 (19.1%) 
2/89 (2.2%) 
B 
71/88 (80.7%) 
40/88 (45.5%) 
19/88 (21.6%) 
4/88 (4.5%) 
C 
(itolizumab
1.6 
34/43 (79.1%) 
18/43 (41.9%) 
12/43 (27.9%) 
0/43 
Week 
52 
Open label arm 
52/59 (88.1%) 
33/59 (55.9%) 
16/59 (27.1%) 
5/59 (8.5%) 
Placebo arm 
28/40 (70.0%) 
21/40 (52.5%) 
12/40 (30.0%) 
4/40 (10.0%) 
(N=177) 
Itolizumab (from 
arm A and B) 
33/39 (84.6%) 
26/39 (66.7%) 
12/39 (30.8%) 
 
3/39 (7.7%) 


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Itolizumab (from 
arm C) 
27/39 (69.2%) 
16/39 (41.0%) 
11/39 (28.2%) 
2/39 (5.1%) 
Note: At Week 12, patients in arm C were crossed over to receive itolizumab 1.6 mg/kg every 2 weeks till Week 
24. Week 
24 to 28 was treatment-free period. From Week 28 to 52, patients in arm C received itolizumab 1.6 mg/kg 
every 12 weeks. n=number of patients with response; N=total number of patients 
Figure 1 represents the proportion of patients at each visit up to Week 28 who achieved PASI 75 by treatment arm. The 
rate of improvement in PASI score was similar in 2 arms (arm A and arm B), though delayed by about 4 weeks for arm 
A, where patients received a lower dose in the first 
4 weeks compared to patients from arm B. After patients in arm C were crossed over to receive itolizumab at Week 12, 
they showed rapid improvement, and by Week 20 the proportion of patients achieving PASI 75 was similar in all arms. 
 


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Figure 1. Proportion of Patients Achieving PASI 75 by study Arm and Visit in the TREAT- PLAQ Study. 
Bars represent exact 95% confidence intervals. 
[Note: At Week 12, patients in arm C were crossed over to receive itolizumab 1.6 mg/kg every 2 weeks till 
Week 24. Week 24 to 28 was treatment-free period]. 
Similar to the improvement in PASI scores, the proportions of patients who achieved PGA score “clear” or 
“minimal” were higher at Week 12 for arm A (20%) and B (16%) than for arm C (5%); but by Week 28, the 
proportions were similar for all three arms (21%, 26% and 23%) (Table 3). Quality of life, as assessed by the 
SF-36 and DLQI score, improved throughout the study. 
Improvement in DLQI scores was consistent with PASI scores. The proportion of patients who reported that the 
disease had only a small or negligible effect on their lives increased in each arm up to Week 28. 
 
Table 3. Summary of Itolizumab Efficacy Data in the TREAT-PLAQ Study: Proportion of Patients with PGA 
Score of “clear” or “minimal” at Week 12, 28 and 52 
Response 
achieved at: 
Proportion of patients achieving PGA response [n/N (%)] 
p 
values 
Arm A 
Arm B 
Arm C 
- 
Total 
Week 12 
16/80 
(20%) 
14/87 
(16.1%) 
2/41 
(4.9%) 
- 
32/208 
(15.4%) 
0.03101 
Week 28 
16/76 
(21.1%) 
22/84 
(26.2%) 
9/39 
(23.1%) 
- 
47/199 
(23.6%) 
- 
- 
Open 
label 
Placebo 
group 
Itolizumab (from 
arm A and B) 
Itolizumab (from 
arm C) 
- 
- 
Week 52 
17/58 
(29.3%) 
12/40 
(30%) 
17/38 
(44.7%) 
9/38 
(23.7%) 
55/174 
(31.6%) 
- 
PGA: Investigator’s global assessment 
n=number of patients with response; N=total number of patients 
1A versus. C; 2B versus. C 
Pharmacokinetic Properties 
The pharmacokinetic (PK) data for itolizumab in psoriasis patients is based primarily on data from the phase 2 
study (Study I). The PK parameters of itolizumab were determined over 8 weeks of treatment and 4 weeks of 
treatment-free follow-up. Itolizumab was administered at doses ranging from 0.4 to 1.6 mg/kg as intravenous 
(IV) infusion. An enzyme-linked immunosorbent assay (ELISA) method was used to measure itolizumab in 
serum samples. 
A linear dose-dependent relationship was observed for various PK parameters after first dose administration 
of itolizumab. The average maximum drug concentration (Cmax) and area under concentration-time curve 
(AUC0-t) values obtained after the first and last infusion of 0.4 mg/kg, 
0.8 mg/kg (administered once every week, once in 2 weeks or once in 4 weeks) and 1.6 mg/kg (administered 
once in 2 weeks or once in 4 weeks) increased in proportion to dose (Table 4). Both AUC0-t and serum trough 
concentration increased with increase in dosage and frequency of administration of itolizumab, indicating 
more accumulation on frequent administration. With multiple administrations (after administration of all 
dosages) dose‐proportional increase were observed in average Cmin. Volume of distribution and clearance 
increased marginally with decrease in frequency of administration. The median half-life (t1/2) obtained after 
the last dosage ranged from 11.72 to 18.51 days across the different dosage-frequency combinations. 
 
Table 4. Mean Pharmacokinetic Parameters (Cmax and AUC0-t) of Itolizumab (IV infusion) Derived 
from Phase 2 Study in Psoriasis Patients. 
Dose 
Dosing 
Cmax (µg/mL) 
AUC0-t (hr.µg/mL) 
(mg/kg) 
interval 
First infusion 
Last infusion 
First infusion 
Last infusion 


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0.4 
Every week 
Every 2 weeks 
8.01 
10.93 
20.98 
15.30 
569.69 
897.30 
4351.25 
2750.49 
0.8 
Every week 
Every 2 weeks 
19.95 
20.03 
29.75 
29.19 
1284.94 
1833.22 
9663.53 
9205.22 
1.6 
Every 2 weeks 
Every 4 weeks 
39.94 
41.02 
49.56 
41.39 
4103.77 
6682.89 
14017.06 
10230.29 
Cmax: Maximum drug concentration; AUC0-t: area under the concentration time curve from time 0 to t 
 
Preclinical Safety Data 
Carcinogenesis, mutagenesis, impairment of fertility 
Long-term animal studies of itolizumab have not been conducted to evaluate carcinogenic potential, mutagenic 
potential or effect on fertility. 
Animal Toxicology and/or Pharmacology 
Results in animal studies revealed that itolizumab does not cross-react with rodent CD6. 
Chimpanzee and baboon were identified as the relevant species; as itolizumab recognizes CD6 in these species. 
However, chimpanzees were not used in further experiments as their use in research is highly restricted as they 
are considered endangered. 
Single- and repeat-dose toxicity studies were conducted in conventional, pharmacologically non- relevant 
species to evaluate any off-target safety indicators. In the single-dose toxicity study, Sprague-Dawley rats were 
administered single injection of itolizumab at 1.25 and 2.5 mg/kg 
(IV). No treatment-related mortalities or clinical toxic signs were observed. Single doses of itolizumab were 
well tolerated in rats; the maximum tolerated dose (MTD) was found to be 2.5 mg/kg. In the repeat-dose 
toxicity study, Cenp:SPRD rats (derived from Sprague-Dawley) were treated with itolizumab at 1.6 and 16 
mg/kg/day for 14 days (IV). No mortality, toxic signs; changes in body weight, changes in rectal temperature, 
or alterations at the injection site were seen. Moreover, there were no significant physiological alterations in 
hematological or biochemical parameters, or macroscopic or histological alterations in parenchymal organs. 
Itolizumab was found to be well tolerated; no observed adverse effect level (NOAEL) was considered to be 
16 mg/kg. However, as the pharmacological target of itolizumab is absent in rats, clinical relevance of these 
toxicity findings is unknown. 
Various toxicity studies were conducted with the murine version of itolizumab (ior t1), which is a murine 
monoclonal antibody with the same antigenic specificity as itolizumab. A single dose acute toxicity was 
conducted with ior t1 in Wistar rats at the dose levels of 6, 30 and 60 mg/kg (IV). No noticeable difference 
was found between control and treatment groups. The MTD was concluded to be 60 mg/kg. In the repeat dose 
toxicity study Wistar rats were administered with ior t1 at the dose levels of 6, 30 and 60 mg/kg body weight 
(IV) in 3 cycles of 5 treatment days. No death or toxic alteration was observed even at the highest dose level. 
The NOAEL of ior t1 was concluded to be 60 mg/kg body weight. In the local cutaneous tolerance test rabbits 
were administered ior t1 jelly at 0.3 and 3 mg/g topically for 35 days. In this study, no morphological, clinical 
or histological alterations were observed in the animal skin. In the dermal irritability study, ior t1 was found 
to be devoid of potential to cause irritation. The significance of results of these nonclinical studies to human 
risk is unknown. 
 
CLINICAL PRTICULARS 
Therapeutic Indications 


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ALZUMAbTM is indicated for the treatment of patients with active moderate to severe chronic plaque psoriasis 
who are candidates for systemic therapy. 
Limitations of Use 
The safety and efficacy of ALZUMAbTM have not been studied in, (a) pediatric patients <18 years old; 
(b) patients with hepatic and renal impairment; (c) pregnancy and, (d) nursing mothers. 
Posology and Method of Administration 
The recommended dose of ALZUMAbTM for the treatment of plaque psoriasis is 1.6 mg/kg given as IV 
infusion once every 2 weeks for 12 weeks, followed by 1.6 mg/kg every 4 weeks up to 24 weeks. 
Prior to initiating ALZUMAbTM and periodically during therapy, patients should be evaluated for active 
tuberculosis and tested for latent infection [see Special Warnings and Precautions for Use and 
Contraindications]. 
ALZUMAbTM is intended for use under the guidance and supervision of a Investigator. The diluted infusion 
solution should be prepared by a trained medical professional using aseptic technique; as follows: 
Calculate the dose and number of ALZUMAbTM vials needed. ALZUMAbTM is provided as 
preservative-free single-use vial for IV infusion. Each vial contains 25 mg of itolizumab (5 mg/mL) in a 
sterile, clear, colorless, preservative-free buffer solution at pH 7.0±0.5 [see Pharmaceutical Particulars]. 
ALZUMAbTM should be administered via IV infusion in 250 mL of 0.9% Sodium Chloride solution 
(normal saline). For this, dilute the appropriate dose of ALZUMAbTM to 250 mL with sterile normal saline. 
Gently mix. 
Fully diluted ALZUMAbTM solution should be allowed to reach room temperature prior to infusion. Before 
use, the fully diluted ALZUMAbTM solution may be stored at room temperature or refrigerated at 2-8ºC 
(36ºF-46ºF) protected from light. ALZUMAbTM is stable in an infusion bag containing 250 mL of normal 
saline for up to 10 hours at room temperature. Do not administer as IV push or bolus. 
The infusion must be administered over a period of not less than 120 minutes and using an infusion set 
with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size of 1.2 µm or less). 
Approximately 50 mL of diluted ALZUMAbTM solution should be administered during the first hour, 
followed by remaining solution (approximately 200 mL) in the next hour. The infusion period can be 
extended up to 8 hours for medical reasons. 
The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion 
solution should not be stored for reuse [see Pharmaceutical Particulars]. 
No physical or biochemical compatibility studies have been conducted to evaluate the co- 
administration of ALZUMAbTM with other agents. ALZUMAbTM should not be infused 
concomitantly in the same IV line with other agents. 
Prior to administration, the solution in the vial should be carefully inspected visually for particulate matter 
and discoloration. If visible opaque particles, discoloration or other foreign particulates are observed, the 
product should not be used. 
Contraindications 
ALZUMAbTM should not be administered to patients having history of severe allergy or known 
hypersensitivity reaction to any component of ALZUMAbTM or any murine proteins. Additionally, 
ALZUMAbTM is contraindicated in patients with any active serious infection [see Special Warnings and 
Precautions for Use]. 
Special Warnings and Precautions for Use 
Infusion-related reactions and hypersensitivity reactions 


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During administration of ALZUMAbTM some patients may develop acute infusion reactions. Symptoms 
may include nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, wheezing, dyspnea, dizziness, 
headache, and hypertension. Infusion reactions are most likely to occur during the first cycle of dosing and 
tend to decrease in severity and frequency upon subsequent infusions. Infusion reactions reported during the 
TREAT-PLAQ study (Study II) were mild to moderate in severity, except in one patient who had delayed 
infusion reaction which was reported as serious adverse event (SAE). In the same patient, adjustment disorder 
anxiety also was reported as SAE [see Undesirable effects]. Acute infusion reactions should be treated using 
the standard of care; and Investigators may need to delay dosing till the patient is stabilized. 
Infections 
Investigators should exercise caution before and during ALZUMAbTM treatment in patients with a history of 
recurrent infections or underlying conditions which may predispose them to serious infections. Patients should 
be closely monitored closely for the development of signs and symptoms of infection during and after treatment 
with ALZUMAbTM, including patients who were evaluated negative for latent tuberculosis infection prior to 
initiating therapy. In case of new infection or reactivation of latent infection during the treatment, 
ALZUMAbTM treatment should be discontinued and immediate treatment in accordance with standard medical 
practice should be instituted. During the TREAT-PLAQ study, one case of tubercular lymphadenitis was 
reported after 4 weeks of itolizumab treatment, in a patient who had prior history of tuberculosis. The patient 
was withdrawn for safety reasons. During the study, one case of septic arthritis was reported; bacterial culture 
and acid-fast bacilli (AFB) culture of synovial fluid were negative and causality was inconclusive [see 
Undesirable Effects]. Overall, ALZUMAbTM did not appear to increase rate of infections in patients compared 
to placebo, during the study. 
ALZUMAbTM has not been studied in patients with active intercurrent infections, or a past history of serious 
infections such as HIV-AIDS or tuberculosis [see Contraindications]. ALZUMAbTM has not been studied in 
the patients having low absolute neutrophil or lymphocyte count (<1500 cell/µL). The effect of ALZUMAbTM 
in these special populations is unknown. Caution should be exercised while administering itolizumab to 
immunocompromised patients with Human Immunodeficiency Virus (HIV), Hepatitis B, Hepatitis C infection 
and patients receiving or received chronic steroid therapy. 
Prior to initiating ALZUMAbTM administration, patients should be screened for active or latent tuberculosis 
infection using Mantoux test and or chest x-ray. 
Use with other biologics 
ALZUMAbTM has not been studied in combination with other biological agents approved for the treatment 
of plaque psoriasis. ALZUMAbTM should not be used with such agents because of the possibility of increased 
immunosuppression and increased risk of infection. 
Vaccination 
No data are available on the response to vaccination with live/attenuated vaccines or on the secondary 
transmission of infection by live vaccines in patients receiving ALZUMAbTM therapy. Based on its 
mechanism of action, ALZUMAbTM may blunt the effectiveness of some immunizations. It is recommended 
that live/attenuated vaccines not be given concurrently with ALZUMAbTM. The patient’s vaccination record 
and the need for immunization prior to receiving ALZUMAbTM should be carefully investigated. The interval 
between vaccination and initiation of ALZUMAbTM therapy should be in accordance with current vaccination 
guidelines. Caution is advised in the administration of live vaccines to infants born to female patients treated 
with ALZUMAbTM during pregnancy, since ALZUMAbTM may cross the placenta. 
Malignancies 
None of the patients on itolizumab treatment developed malignancies during the clinical trials. 
Drug Interactions 


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Drug interaction studies have not been performed with ALZUMAbTM. 
Pregnancy and Lactation 
Use in Pregnancy 
As with other IgG antibodies, itolizumab may cross the placenta during pregnancy. It is not known whether 
ALZUMAbTM can cause fetal harm when administered to a pregnant woman, or whether it can affect 
reproductive capacity or fertility. Animal reproduction studies have not been conducted with ALZUMAbTM 
as it does not recognize peripheral blood mononuclear cells within species other than humans, baboons and 
chimpanzees [see Preclinical Safety Data]. 
The available clinical experience is too limited to exclude a risk, and administration of 
ALZUMABTM is therefore not recommended during pregnancy. 
Lactation 
It is not known whether itolizumab is excreted in human milk or absorbed systemically after ingestion. Because 
many drugs and immunoglobulin are excreted in human milk, and because of the potential for serious adverse 
reactions in nursing infants from ALZUMAbTM, a decision should be made whether to discontinue nursing or 
to discontinue the drug, taking into account the importance of the drug to the mother. 
Undesirable 
Effects 
Clinical trial experience 
Safety data of ALZUMAbTM has been derived from 2 randomized, multicentre studies in patients with chronic 
plaque psoriasis. Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs and 
may not predict the rates observed in the broader patient population in clinical practice. 
Study I was a randomized, single-blind, parallel-group, phase 2 study in 40 patients. Overall, 
123 adverse events (AEs) were reported during the study. The most common AE was chills (5.69%), followed 
by pyrexia (4.88%). There was a relatively higher incidence of AEs with higher frequency of dosing at each 
dose. Numerically, the largest number of AEs (n=24) was reported for the highest dose administered in the trial 
(1.6 mg/kg every 2 weeks). 
Twenty nine out of 40 (72.50%) patients in the study reported at least one AE during the study. Seventy-three 
out of 123 (59.35%) AEs were graded as mild, 46 (37.39%) were graded as moderate and 4 (3.25%) were 
graded as severe. There were 4 SAEs reported during the study. Three out of 4 SAEs reported were related to 
musculoskeletal and connective tissue disorders (e.g. arthralgia, other musculoskeletal pain and osteonecrosis) 
and one was erythrodermic psoriasis. There were 16 acute and 4 possible delayed infusion reactions. All these 
reactions were mild to moderate and the patients recovered completely. The incidence of infusion reactions was 
higher during the initial doses and decreased with subsequent dosing. All infusion reactions were mild to 
moderate in severity. There were no significant changes in general examination and vital signs from baseline 
to the end of trial. Immunogenicity analysis detected one sample from one patient (0.4 mg/kg once in 2 weeks) 
with high-titre antibody response at Week 12. However, the immunogenic response did not correlate with any 
clinical adverse event or impact the PK profile. 
Study II (TREAT-PLAQ) was a double-blind, placebo-controlled, one-way crossover phase 3 study in 225 
patients. Overall, there were 289 AEs reported in 111 (49.8%) of the 223 patients in the safety population (i.e. 
patients who received at least one infusion) during 52-week treatment period. Sixty-six patients (29.6%) 
patients had mild AEs, 34 (15.2%) had moderate AEs, and 11 (4.9%) had severe AEs. The overall incidence of 
AEs and related AEs was not meaningfully different between patients randomized to treatment arms A, B and 
C. Overall incidence of AEs was 50%, 47.8% and 53.5% in treatment arm A, B and C, respectively. Incidence 
of related AEs was 26.7%, 28.9% and 30.3%, respectively. The most frequently reported AEs (in ≥5% of 
patients) were infusion-related reactions, pyrexia, upper respiratory tract infection and pruritus (Table 5). 
A total of 30 (13.5%) patients had AE that led to change in administration of study drug. Two (0.9%) patients 
had a decrease in dosage, 19 (8.5%) temporarily discontinued the study drug, 2 (0.9%) patients permanently 
stopped the study drug and 7 (3.1%) patients were withdrawn from the study. 


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The most frequently reported AEs (those that occurred in >5% of patients overall or in any individual treatment 
arm), in decreasing order, were infusion-related reactions, pyrexia, upper respiratory tract infection and pruritus 
(Table 5). In addition to these, diarrhea was reported in 6 (6.7%) patients in arm B. Of the total enrolled 223 
patients, 3 (15.2%) patients had at least one acute infusion reaction during 52-week of treatment period. The 
treatment arms A and B had a slightly higher rate of acute infusion reactions (20% and 16.7%, respectively) 
compared to arm C (11.6%) during 52-week treatment period [see Special Warnings and Precautions for Use]. 
Table 5. Most Frequently Occurring Adverse Events (in >5% of Patients) in the TREAT-PLAQ Study (Week 1-
52). 
 
 
 
 
 
 
 
 
 
 
 
 
n=patients with adverse effect; N=total number of patients 
Infection 
Several immunomodulatory agents approved for psoriasis (such as anti-TNF monoclonal antibodies) are 
known to increase the risk of infections. In the TREAT-PLAQ study, patients were monitored for infections 
(summarized in Table 6). In general, itolizumab did not appear to increase the rate of infections as compared 
to placebo. During the placebo-controlled period, (Weeks 1-12) the proportion of patients with at least one 
infection was higher in the placebo arm (18.6%) than in arms A (11.1%) or B (8.9%). Over the course of the 
study, a total of 40 (17.9%) patients had at least one infection; 26 (11.7%) patients in the first 12 weeks and 
19 (8.5%) patients in Weeks 13 to 52 (5 patients had an infection in both periods). 
 
Table 6. Incidence of Infections in TREAT-PLAQ Surveillance. 
Study Period 
Number of Patients (%) 
Arm to Which Patient was Initially 
Randomized 
Total 
Arm A 
Arm B 
Arm C 
Overall 
16 (17.8) 
16 (17.8) 
8 (18.6) 
40 (17.9) 
Weeks 1-12 
10 (11.1) 
8 (8.9) 
8 (18.6) 
26 (11.7) 
During the TREAT-PLAQ study, one case of septic arthritis was reported 8 months after the start of treatment, 
which was deemed related to the study drug by the investigator. However, bacterial culture and AFB culture of 
synovial fluid were negative. Total and differential counts of the patient were stable and in normal range 
throughout the study. 
There was 1 case of tubercular lymphadenitis was observed after 4 weeks of treatment (5 doses of itolizumab, 
total dose of 3.2 mg/kg) in a patient who had a history of tuberculosis (15 years prior). The patient had WBC 
and differential counts in the normal range throughout the study participation. The patient was withdrawn 
from the study for safety reasons. All other infections reported were either mild or moderate in severity. 
Vital signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate, mean and median pulse rates and 
temperature) were stable throughout the study. 
Immunogenicity 
Preferred Term 
Arm A 
n (%) 
Arm B 
n (%) 
Arm C 
n (%) 
Total 
n (%) 
N=90 
N=90 
N=43 
N=223 
All Adverse Events 
Gastrointestinal disorders 
Diarrhoea 
0 
6 (6.7) 
1 (2.3) 
7 (3.1) 
General disorders and administration site conditions 
Infusion related reaction (acute) 
18 (20) 
15 (16.7) 
5 (11.6) 
38 (15.2) 
Infusion related reaction (delayed) 
2 (2.2) 
5 (5.6) 
1 (2.3) 
8 (3.6) 
Pyrexia 
9 (10) 
8 (8.9) 
5 (11.6) 
22 (9.8) 
Infections and infestations 
Upper respiratory tract infection 
2 (2.2) 
10 (11.1) 
5 (11.6) 
17 (7.6) 
Skin and subcutaneous tissue disorders 
Pruritus 
3 (3.3) 
5 (5.6) 
4 (9.3) 
12 (5.4) 


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The human anti-humanized antibody (HAHA) response to itolizumab was evaluated through analysis of 
immunogenicity of itolizumab at Weeks 4, 12, 28, and 52 in the TREAT-PLAQ study. Positive HAHA 
responses were observed in 51 (23.2%) patients through the study (23 from arm A, 19 from arm B and 9 from 
arm C). In arm C, 7 patients were positive prior to dosing (during the placebo-controlled phase) and 2 patients 
were positive after the crossover phase. Fourteen patients had positive titre at visit 1 (prior to dosing with 
itolizumab). 
There were a few incidences of positive HAHA response during the study. It is not known whether the HAHA 
detected were neutralizing or not; although positive immunogenic response in patients did not correlate with 
either infusion reactions or decreased efficacy. 
Clinical laboratory abnormalities 
Overall, there were no clinically meaningful differences between treatment arms with respect to the 
proportion of patients with abnormalities in hematology and clinical chemistry. There were 31 abnormal 
laboratory values that were reported as AEs in 18 patients. Twenty-six (83.9%) out of the 31 AEs were mild 
and 5 (16.1%) were moderate. Twenty-two (71%) of the 31 abnormal laboratory values were reported in the 
first 12 weeks of the study and 20 (64.5%) were related to different lipoprotein findings. 
Serious adverse events and deaths 
During the TREAT-PLAQ study, 5 SAEs were reported in 4 (1.8%) patients (all on itolizumab) during the 
placebo controlled phase. Four of the 5 SAEs occurred within the first 12 weeks and 1 SAE occurred during the 
randomized withdrawal phase (after Week 28). The events were dermatitis exfoliative, erythrodermic psoriasis, 
arthritis, infusion-related reaction and adjustment disorder with anxiety. Two of the 5 SAEs (dermatitis 
exfoliative and erythrodermic psoriasis) were determined to be unlikely related to the study drug. Remaining 3 
SAEs were determined to possibly or certainly related. Of three SAEs, 2 (infusion-related reaction and 
adjustment disorder anxiety) were reported in the same patient. The third SAE was classified as septic arthritis. 
It was reported 8 months after the start of itolizumab treatment (6 months treatment followed by single dose of 
placebo). The event occurred 3 months after the last dose of itolizumab and was deemed related to the study 
drug by the investigator. However, bacterial culture and AFB culture of synovial fluid were negative. 
No deaths were reported during the course of the study. 
Other AEs that do not appear in Special Warnings and Precautions for Use or Undesirable effects sections that 
occurred at a rate of at least 1% and at a higher rate in the itolizumab treated patients than the placebo group 
during the placebo-controlled period of TREAT-PLAQ study 
(Study II) irrespective of relationship to the study products are listed below: 
Gastrointestinal disorders: diarrhoea, toothache, vomiting, gastritis, gastrointestinal inflammation General 
disorders and administration site conditions: Infusion-related reactions (acute and chronic), oedema peripheral, 
pain, chest pain. 
Infections and infestations: abscess, folliculitis, gastroenteritis, lymphadenitis bacterial, lymph node tuberculosis, 
oral herpes, pyrexia, urinary tract infection, rhinitis, tooth abscess Metabolism and nutrition disorders: 
dehydration, hepatic steatosis, hypertriglyceridemia. 
Musculoskeletal and connective tissue disorders: musculoskeletal pain, pain in extremity, arthralgia, back pain. 
Nervous system disorders: headache, neuropathy peripheral, cerebrovascular accident. 
Psychiatric disorders: Adjustment disorder with anxiety. 
Renal and urinary disorders: dysuria. 
Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain, rhinorrhea. 
Skin and subcutaneous tissue disorders: psoriasis, keloid scar, dermatitis exfoliative, pruritis, 
erythrodermic psoriasis. 
Overdose 
Doses up to 1.6 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting 
toxicities. During the TREAT-PLAQ study (study II), one patient was overdosed by 23.2 mg with the cumulative 
dose of 50 mg during the first week of itolizumab treatment. However, no AE was observed and patient was 
normal. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of 
adverse reactions or effects and appropriate symptomatic treatment instituted immediately. 
PHARMACEUTICAL PARTICULARS 
List of Excipients 


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Monobasic sodium phosphate, dibasic sodium phosphate (anhydrous equivalent), sodium chloride, polysorbate 
80 and water for injection. ALZUMAbTM contains no antibacterial preservatives. Incompatibilities: In the 
absence of compatibility studies, ALZUMAbTM must not be mixed with other medicinal products. 
Shelf Life: 36 months 
Storage and Precautions 
Store at a temperature between 2°C and 8°C. KEEP OUT OF REACH OF CHILDREN. 
 
Nature and Contents of Container 
Pack size: 25 mg/5 mL 
ALZUMAbTM is packed in 6R clear glass vial (USP type 1) closed with a chlorobutyl rubber stopper 
and sealed with flip-off seals (aluminium rim with plastic flip-off lid). 
Special Precautions for Disposal and Handling 
Do not administer as IV push or bolus. 
Prior to infusion, fully diluted ALZUMAbTM solution should be allowed to reach room 
temperature. 
Prior to administration, the product should be visually inspected for opaque particles, discoloration or other 
particulates. 
The product should not be used, and discarded if: the seal is broken, visible opaque particles, discoloration or 
other foreign particulates are observed, it may have been accidently frozen, or there has been refrigerator failure. 
Any unused product or waste material should be disposed of in accordance with local 
requirements. 
 
MANUFACTURED BY 
Biocon Biologics India Limited, 
Block No. B1, B2, Q13 of Q1 and W20 & Unit S18, 1st floor, Block B4, 
Special Economic Zone, Plot No. 2, 3, 4 &5, 
Phase IV, Bommasandra-Jigani Link Road, Bommasandra Post, 
Bengaluru - 560099, India 
 
MARKETED BY 
Biocon Biologics India Limited, 
Biocon House, Semicon Park, Tower II, 
Electronics City Phase II, Bangalore – 560100, India. 
 
®– Registered Trademark. 
Leaflet generated December 2019. 
To report adverse effects call Toll Free No: 1800 102 9465 or e-mail us at 
DrugSafety@biocon.com. 

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SAP Final, Date: 29-JUN-2020 
Confidential 
Final 
Page 1 of 40 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Clinical Trial Protocol 
Identification No: 
ITOLI-C19-02-I-00 
 
Title: 
 A Multi-Centric, Open label, Two Arm Randomized, Pivotal Phase2 
Trial to Study the Efficacy and Safety of Itolizumab in COVID-19 
Complications. 
 
Trial Phase: 
Pivotal Phase II 
 
 
Name of the Drug: 
Itolizumab (ALZUMAb™) 
 
 
Clinical Trial Protocol Date 
and Version: 
3-June-2020/ Version 5.0 
 
Statistical Analysis Plan Date 
and Version: 
29-June-2020/ Final 
 
 
 
Sponsor: 
 Biocon Biologics India Limited, Biocon House, Electronic 
City, Bengaluru – 560100, India 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is a confidential communication of Biocon Biologics India Limited. Acceptance of this document 
constitutes an agreement by the recipient(s) that no unpublished information contained herein will be published or disclosed without 
prior written approval from Biocon Biologics India Limited. 


Biocon Biologics India Limited 
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Confidential 
Final 
Page 2 of 40 
 
 
 
 
 
 
SIGNATURE PAGE 
 
Prepared by 
 
Anjaiah Kalva 
Deputy Manager (CDMA Biostatistics) 
Biocon Biologics India Limited 
Anjaiah 
Kalva 
 
Digitally signed 
by Anjaiah Kalva 
Date: 2020.06.30 
10:09:02 +05'30' 
 
  
 
Signature 
Date 
 
 
 
Reviewed & Approved by 
 
Ashwani Marwah 
Sr. Manager (CDMA Biostatistics) 
Biocon Biologics India Limited 
 
Marwah 
Digitally signed by 
Ashwani Marwah 
Date: 2020.06.30 
10:14:57 +05'30' 
 
  
 
Signature 
Date 
 
 
 
 
Subramanian L 
Digitally signed by Subramanian 
General Manager (CDMA Medical Sciences) Subramanian Loganathan Loganathan 
Biocon Biologics India Limited 
Date: 2020.06.30 12:30:16 +05'30' 
 
  
 
Signature 
Date 
Ashwani 


Biocon Biologics India Limited 
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Confidential 
Final 
Page 3 of 40 
 
 
 
Table of Contents 
List of abbreviations ..................................................................................................................................... 6 
1 
Purpose .................................................................................................................................................. 7 
2 
Responsibility ....................................................................................................................................... 7 
3 
Study Objectives ................................................................................................................................... 7 
3.1 
Trial Objectives ............................................................................................................................. 7 
3.1.1 
Primary Objectives ................................................................................................................ 7 
3.1.2 
Secondary Objectives ............................................................................................................ 7 
3.2 
Outcome Measures ........................................................................................................................ 8 
3.2.1 
Primary endpoint ................................................................................................................... 8 
3.2.2 
Secondary endpoints ............................................................................................................. 8 
4 
TRIAL DESIGN AND DESCRIPTION ............................................................................................... 9 
4.1 
Trial Design .................................................................................................................................. 9 
4.2 
Subject Selection ........................................................................................................................... 9 
4.3 
Inclusion Criteria .......................................................................................................................... 9 
4.4 
Exclusion Criteria ......................................................................................................................... 9 
4.5 
Sample Size, Treatment Assignment, Randomization ................................................................ 10 
5 
Protocol Deviation .............................................................................................................................. 10 
6 
General Aspects for Statistical Methods ............................................................................................. 10 
7 
Analysis Population ............................................................................................................................ 11 
8 
Demography other baseline Characterstics ......................................................................................... 11 
9 
Efficacy Evaluation ............................................................................................................................. 11 
10 
Other Evaluations ............................................................................................................................ 13 
11 
Interim Study Report ....................................................................................................................... 13 
12 
Key Definitions ............................................................................................................................... 13 
13 
Programming Considerations, Listing of Tables, Figures & Format, Software detail .................... 14 
14 
Tables and mock shells ................................................................................................................... 15 
14.1.1 
Screening Failures ....................................................................................................................... 15 
14.1.2 
Disposition of Patients ................................................................................................................ 16 
14.1.3 
Subject Disposition by Centre ..................................................................................................... 17 
14.1.4 
Summary of Demographic Characterstics................................................................................... 17 
14.1.5 Summary of Concomitant Medication by treatment group .............................................................. 18 
14.1.6 
Summary of Medical History ...................................................................................................... 18 


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14.1.7 
Summary of Vital Parameters and change from Baseline ........................................................... 19 
14.1.8 
Summary of Laboratory Test Results and Change from Baseline: Hematology ........................ 20 
14.1.9 
Summary of Laboratory Test Results and Change from Baseline: Biochemistry ....................... 20 
14.1.10 Hospitalization ............................................................................................................................... 22 
14.1.11 
Duration of hospitalization and ICU stay ................................................................................ 23 
14.1.12 
Summary of Study Treatment: Itolizumab treatment details in Arm A .................................. 24 
14.1.13 Summary of BSC treatment details in both arms ........................................................................... 25 
14.2 Primary outcome measures ................................................................................................................. 26 
14.2.1 Primary Outcome Measures ............................................................................................................. 26 
14.2.2 Proportion of patients needed intubation during the study .............................................................. 26 
14.2.3 Reduction in proportion of patients who need Non-invasive ventilation ......................................... 26 
14.2.4 Reduction in proportion of patients who need NRBM .................................................................... 27 
14.2.5 Reduction in proportion of patients who need Face Mask ............................................................... 27 
14.2.6 Reduction in proportion of patients who need High Flow Nasal Oxygen ....................................... 28 
14.2.7 One-month Mortality Rate ............................................................................................................. 28 
14.2.8 Change in inflammatory markers before and after dosing in Treatment ARM A .......................... 28 
14.2.9 Survival status .................................................................................................................................. 29 
14.2.10 Summary of Oxygen and SOFA analysis ...................................................................................... 29 
14.2.11 Ordinal Scale: No and Proportion of patient reduced by 1 or more points .................................... 30 
14.2.12 Improvement in respiratory rate ..................................................................................................... 30 
14.3 Safety Analysis ................................................................................................................................... 31 
14.3.1 Summary of Subjects with TEAEs by treatment group ................................................................... 31 
14.3.2 Treatment Emergent Adverse Event (TEAE) by SOC and PT ........................................................ 32 
14.3.3 Treatment Emergent Adverse Event (TEAE) by severity ................................................................ 33 
14.3.4 Treatment Emergent Adverse Event (TEAE) related to study drug ................................................ 33 
14.3.5 Treatment Emergent Adverse Event (TEAE) by Outcome .............................................................. 33 
15. Supplementary Tables ........................................................................................................................... 34 
16. Listings .................................................................................................................................................. 35 
Listing 16.1.1 Subjects Inclusion ................................................................................................................ 35 
Listing 16.1.2 Subjects Exclusion ............................................................................................................... 35 
Listing 16.1.3 Demographic data ................................................................................................................ 36 
Listing 16.1.4 Medical History ................................................................................................................... 36 
Listing 16.1.5 Concomitant Medication...................................................................................................... 36 


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Listing 16.1.6 Disposition of Subjects ........................................................................................................ 36 
Listing 16.1.7 Vital Parameters ................................................................................................................... 37 
Listing 16.1.8 Biomarker ............................................................................................................................ 37 
Listing 16.1.9 Haematology ........................................................................................................................ 37 
Listing 16.1.10 Biochemistry ...................................................................................................................... 37 
Listing 16.1.13 Chest X Ray/CT Scan ........................................................................................................ 39 
Listing 16.1.14 Adverse Event (Part1) ........................................................................................................ 39 
Listing 16.1.15 Adverse Event (Part-2) ...................................................................................................... 39 
Listing 16.1.16 Hospitalization ................................................................................................................... 39 
Listing 16.1.17 Survival Status ................................................................................................................... 40 
Listing 16.1.18 SOFA Score ....................................................................................................................... 40 
Listing 16.1.19 Ordinal Scale ..................................................................................................................... 40 
Figure 1 Disposition by centres .................................................................................................................. 40 
Figure 2 PaO2/FiO2 ratio ............................................................................................................................ 40 


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List of abbreviations 
 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALT/SGPT/ 
ALAT 
Alanine Transaminase /Serum Glutamic Pyruvic Transaminase/ 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
AST / 
SGOT/ASAT 
Aspartate Transaminase/ Serum Glutamic Oxaloacetic 
Transaminase/Aspartate Aminotransferase 
ART 
Adverse Reaction Terminology 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CRP 
(C-Reactive Protein) Level 
ECG 
Electrocardiogram 
EOS 
End of Study 
EoT 
End of Trial 
eCRF 
Electronic case report form 
FiO2 
Fraction of Inspired Oxygen 
i.v. 
intravenous(ly) 
IMP 
Investigational Medical Product 
IRC 
Independent Review Committee 
IE 
In evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per Protocol 
PaO2 
Partial Pressure of Oxygen 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SAP 
Statistical Analysis Plan 
UNK 
Unknown 
US 
Ultrasound 
V 
Visit 
Wk 
Week 


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1 
Purpose 
The purpose of this statistical analysis plan (SAP) is to assess the efficacy and safety of Itolizumab 
administered in patients with COVID-19 complications in comparison with the Best of Care that 
will be included in the clinical study report. And this document is based on protocol version 5.0, 
3rd June 2020. SAP will ensure that the data listings, summary tables and figures are complete; 
and the statistical methodologies used are appropriate to allow valid conclusions in line with the 
study’s objectives. This document will be appended to the clinical study report (CSR). The 
statistical analyses will be performed in accordance with the ICH-E9 guidelines “Statistical 
Principles for Clinical Trials” and relevant guidelines from Central Drugs Standard Control 
organization (CDSCO). If circumstances arise during the study such that more appropriate analytic 
procedures become available, this statistical analysis plan (SAP) may be revised. Any revisions to 
the SAP (both alternative and additional methods) will be made prior to database lock and reasons 
for such revisions will be described in the final Clinical Study Report (CSR). 
 
2 
Responsibility 
 
Biocon Biologics India Limited/Designated CRO will be responsible for the conduct of statistical 
analyses, and the production and quality control of all tables, figures and listings). 
 
3 
Study Objectives 
Coronavirus disease 2019 (COVID-19) progresses to respiratory complications as consequence of 
the exaggerated immune response of the host, producing a pro-inflammatory cytokine storm 
syndrome (i.e.: IL-6, TNF) and cytopenia, with a high mortality rate. Emergency treatments aiming 
to reduce individual cytokines (IL-6 and IL-1) specifically [or indirectly (JAK inhibitors and CCR5 
antagonists) have shown survival benefit in patients with hyperinflammation, without increased 
adverse events. However, not being sufficient to reduce the rising mortality by COVID-19 other 
interventions to immunomodulate the life-threatening hyperinflammation are urgently needed. 
Therefore, the proposal for use of an anti-CD6 monoclonal antibody (Itolizumab) for the treatment 
of the COVID-19 complications (cytokine storm syndrome). 
 
3.1 
Trial Objectives 
 
3.1.1 
Primary Objectives 
To study the efficacy and safety of adding Itolizumab in patients with Moderate to Severe COVID- 
19 complications (Cytokine Release Syndrome). 
 
3.1.2 
Secondary Objectives 
To study the effect of immunomodulation by Itolizumab and its correlation to clinical 
improvement by evaluating biomarker data (IL6, TNF-a, IL17, IL1, Interferon -A etc.) before and 
after Itolizumab treatment 


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3.2 
Outcome Measures 
 
3.2.1 
Primary endpoint 
1. Proportion of patients with deterioration of lung function as measured by*: 
• 
Stable SpO2 without increasing FiO2 
• 
Stable PaO2 without increasing FiO2 
2. Reduction of endo-tracheal intubation rate, measured as rate of patients needing 
intubation* 
3. Reduction in proportion of patients who need* 
• 
Non-invasive ventilation 
• 
Invasive mechanical ventilation 
• 
High flow nasal oxygen 
4. Time of duration of mechanical ventilation or time to end of mechanical, measured as 
elapsed time from the start date of mechanical ventilation to the weaning date, for patients 
needing intubation* 
5. One-month mortality rate between the two arms* [ Time Frame: up to 1 month ] 1-month 
mortality is defined as the ratio of patients who will live after 1month from study start out 
of those registered at baseline 
6. Change in inflammatory markers like CRP (C-reactive protein) level, d-Dimer, ferritin etc. 
[ Time Frame: Arm A; baseline, during treatment (Before every dose and 12 to 24 h after 
every dose) up to 1 month, Arm B: baseline, 12 to 24 h and approx. 7 and 14 days after 
randomization ] 
* Applicable for both the arm 
 
3.2.2 
Secondary endpoints 
1. 
Biomarkers (IL-6, TNF-a, IL1, IL17, etc…) [ Time Frame: Arm A; baseline, during 
treatment (Before every dose and 12 to 24 h post dose) up to 1 month, Arm B; baseline, 
12 to 24 h and approx. 7 and 14 days after randomization ] 
2. 
Lymphocyte count [ Time Frame: Arm A; baseline and before every dose up to 1 month, 
Arm B; baseline, approx. 7 and 14 days after randomization ] Lymphocyte count assessed 
by routinely used determination of blood count 
3. 
PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F 
ratio) [ Time Frame: Arm A; baseline, during treatment (Before every dose and 48 h post 
dose) up to 1 month, Arm B: baseline, 48 h and approx. 7 and 14 days after randomization] 
calculated from arterial blood gas analyses (values from 300 to 100) 
4. 
Number of participants with treatment-related side effects as assessed by Common 
Terminology Criteria for Adverse Event (CTCAE) version 5.0 [ Time Frame: during 
treatment and up to 30 days after the last treatment dose ]* graded according to CTCAE 
citeria (v5.0) 
5. 
Radiological response [ Time Frame: at baseline, after seven days and if clinically 
indicated (up to 1 month) ]* Thoracic CT scan or Chest XR 
6. 
Duration of hospitalization [ Time Frame: from baseline up to patient's discharge (up to 
1 month) ]* Days of hospitalization and ICU 


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7. 
Remission of respiratory symptoms [ Time Frame: up to 1 month ]* time to independence 
from non-invasive mechanical ventilation calculated in days 
8. 
Remission of respiratory symptoms [ Time Frame: up to 1 month ]* time to independence 
from oxygen therapy in days 
* Applicable for both arms 
 
4 
TRIAL DESIGN AND DESCRIPTION 
4.1 
Trial Design 
It is a Multi-Centric, Open label, Two Arm Randomized, Pivotal Phase 2 Trial to Study the 
Efficacy and Safety of Itolizumab in COVID-19 complications. Patients who have tested positive 
for virological diagnosis of SARS-CoV2 infection (PCR) are planned to be randomised for 
enrolment from various centres in India. All eligible patients entering into the study will be 
randomized in 2:1 ratio to receive the treatment A/ B respectively. 
 
4.2 
Subject Selection 
 
Patients who have tested positive for virological diagnosis of SARS-CoV2 infection (PCR) are 
planned to be randomised for enrolment from various centres in India. 
 
4.3 
Inclusion Criteria 
1. Male or female adults above 18 years (not tested in children yet) 
2. Informed consent for participation in the study 
3. Confirmed virological diagnosis of SARS-CoV2 infection (RT-PCR) 
4. Hospitalized due to clinical worsening of COVID-19 infection 
5. Oxygen saturation at rest in ambient air ≤94% 
6. Patients who are in moderate to severe ARDS as defined by PaO2/Fio2 ratio of < 200 or 
more than 25% deterioration from the immediate previous value. 
7. Baseline serum ferritin level ≥ 400 ng/mL or IL-6 levels greater than 4 times ULN, if 
known 
Note: Either of Inclusion number 6 or 7 is required for inclusion of the patient into the study. Since 
there is logistical delay in getting results in time, biomarker data as inclusion criteria may be used 
if already known. 
 
4.4 
Exclusion Criteria 
1. Known severe allergic reactions to monoclonal antibodies 
2. Active tuberculosis (TB) infection 
3. History of inadequately treated tuberculosis or latent tuberculosis 
Note:. Latent tuberculosis should be excluded based on history, physical examination and chest x 
ray before dosing (day 1). QuantiFERON TB also should be performed, however considering 
criticality of patient condition, patient can be dosed without QuantiFERON TB test results. If 


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QuantiFERON TB test is positive, then continuation of patient in the study is investigator’s 
discretion considering benefit-risk evaluation with the sponsor. 
4. In the opinion of the investigator, progression to death is highly probable, irrespective of 
the provision of treatments 
5. Patient on invasive mechanical ventilator support. 
6. Have received oral anti-rejection or immune-suppressive drugs within the past 6 months 
Note: Patient receiving oral anti-rejection or immune-suppressive drugs regularly in the last 6 
months will be excluded. Patient will be included if received short course of steroids. 
7. 
Participating in other drug clinical trials like using anti-IL-6 therapy like tocilizumab 
(participation in COVID-19 anti-viral trials may be permitted if approved by Sponsor) 
8. Patient on treatment of anti-IL-6 or plasma therapy as a part of supportive care 
9. Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination 
10. Any serious medical condition or abnormality of clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study 
11. Patients with known history of Hepatitis B, Hepatitis C or HIV 
12. Absolute Neutrophils count (ANC) <1000 / mm3 
13. Platelet count <50,000 / mm3 
14. Absolute Lymphocyte count (ALC): <500/mm3 
Note: ANC, ALC and platelet counts can be done in local lab in the hospital. 
 
4.5 
Sample Size, Treatment Assignment, Randomization 
Approximately 30 patients are considered sufficient to explore the study objectives and will be 
included in this study (number of patients may be increased if there is benefit observed in initial 
cohort of patients. There is no formal sample size calculation estimated). All eligible patients 
entering into the study will be randomized in 2:1 ratio to receive the treatment A/ B respectively. 
A computer derived randomization schedule is planned to be generated using appropriate system 
e.g. SAS to assign patient to treatment groups. Randomization will be central and appropriate 
system (e.g. remote telephone based, computer-based email, sealed envelope) will be used to 
distribute randomization schedule to the site Note: If the patient is randomised to Arm A and is 
not initiated itolizumab or not administer one full infusion, is then not considered randomized. The 
same randomisation code will be used for the subsequent subject in that particular site. 
 
5 
Protocol Deviation 
Deviations from the protocol, including deviations of inclusion/exclusion criteria will be assessed 
as ‘major’ or ‘minor’ in agreement with Medical Team. Refer to “Guidance Document for Protocol 
Deviation Reporting and Specifications” for details. All protocol deviations will be appropriately 
captured in CSR 
 
6 
General Aspects for Statistical Methods 
In general, metric variables and derived parameters will be presented using descriptive summary 
statistics including arithmetic mean, standard deviation, median, minimum and maximum. 


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Categorical variables will be presented using descriptive summary statistics including number of 
patients and percentages. Percentages of patients will be based on non-missing values. The 
presentation will be by treatment group. Individual values as well as minimum and maximum will 
be presented with the same number of decimal places as the raw data. Derived parameter will have 
as many decimal places as the measured number with the smallest number of decimal places. 
Descriptive statistics, such as arithmetic/geometric mean and median will be presented with an 
additional decimal place and standard deviation with two additional decimal places as the raw or 
derived data. All relevant subject data will be included in the listings; and all subjects entered into 
the database will be included in subject data listings .SAS 9.4 or any other validated software will 
be used for analysis purpose and generating Tables, Listings & Figures. P-values less than 0.05 
may be reported as statistically significant. 
The formatting of the final version of a table, figure, or listing may differ from what is presented 
in the mock shell or the presentation of the results may be changed, however the key content will 
remain unchanged. dditional tables, figures, and listings may be generated to supplement the 
planned output. 
 
7 
Analysis Population 
ITT/FAS population: Patients randomized (in Arm B) and received at least one full dose of 
Itolizumab (in Arm A) 
Safety population: Patients randomized (in Arm B) and received partial or full dose of Itolizumab 
(in Arm A) 
 
8 
Demography other baseline Characterstics 
Demographic characteristics including age, gender, race, and ethnicity will be summarized for 
ITT/FAS populations. Baseline is defined as the last observed value/data before the patient 
receives study drug for the first time or randomized (in Arm B) 
Vital signs such as height, weight, pulse, temperature, respiratory rate, systolic blood pressure, 
diastolic blood pressure, PaO2/FiO2, FiO2, SpO2, mean arterial pressure & GCS score will be 
summarized. 
Medical history, Physical Examination & concomitant medications will be summarized using 
counts and percentage. Additionally, prognostic markers and few key laboratory parameters will 
be summarized. 
 
9 
Efficacy Evaluation 
Primary Efficacy Evaluation 
Proportion of patients with deterioration of lung function as measured by Stable SpO2 without 
increasing FiO2 and Stable PaO2 without increasing FiO2 will be summarized using count and 


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percentage. The difference between two proportion with its 95% Confidence interval and 
associated p-values may be presented, if p-value is less than 0.05 it can be concluded that there is 
a statistically significant difference between two proportions. 
Reduction of endo-tracheal intubation rate, measured as rate of patients needing intubation will be 
summarize using descriptive statistics. 
Reduction in proportion of patients who need/ Non-invasive ventilation / Invasive mechanical 
ventilation/high glow nasal oxygen will be summarized using count & percentage. 
One-month mortality rate between the two arms will be summarized. The difference between two 
rates with its 95% Confidence interval and associated p-values may be presented, if p-value is less 
than 0.05 it can be concluded that there is a statistically significant difference between two-rates. 
Change in inflammatory markers like CRP (C-reactive protein) level, d-Dimer, ferritin etc will be 
summarize with descriptive statistics. Change from Baseline may be presented along with 95% CI. 
 
Secondary Efficacy Evaluation 
 
Biomarkers (IL-6, TNF-a, IL1, IL17, etc…) will be summarize using summary statistics. 
Lymphocyte count will be summarized using count & percentage. 
PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F ratio) 
calculated from arterial blood gas analyses. Radiological response will be summarized in 
descriptive manner. 
Duration of hospitalization will be summarized using descriptive statistics. 
Time to independence from non-invasive mechanical ventilation and from oxygen therapy will be 
summarize using summary statistics. 
Biomarkers (IL-6, TNF-a, IL1, IL17, etc…) Lymphocyte count, CRP (C-reactive protein) level, 
PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F ratio), 
will be summarized with descriptive statistics. Change from Baseline will be presented along with 
95% CI for the difference between two treatments will be reported. 
Radiological response, Duration of hospitalization & Remission of respiratory symptoms will be 
summarized using descriptive statistics. 
Number of participants with treatment-related side effects as assessed by Common Terminology 
Criteria for Adverse Event (CTCAE) version 5.0 graded according to CTCAE criteria (v5.0) will 
be summarized based on frequency and proportion of total subjects, by system organ class and 
preferred term. Proportion of subjects with IRR in both the arm will be presented. An overall 
summary of deaths will be presented by treatment arms. 


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10 
Other Evaluations 
Additional Safety Evaluation 
Additional safety analysis will be provided by treatment group, by severity, by outcome and related 
to study drug. Events will be summarized with descriptive statistics (count & percentage). 
Laboratory Evaluations 
For haematology and biochemistry variables, descriptive summaries of observed values and 
changes from baseline will be presented by treatment arm. Numerical variables will be described 
by number of subjects, mean, standard deviation, median, minimum and maximum and categorical 
variables will be described by number and percentage. 
Vital Signs and Physical examination 
Descriptive statistics of each vital signs parameter will be presented for the Safety Population, 
showing the observed visit and change from baseline to each visit value. These summaries statistics 
(N, mean, SD, median and Min, Max) will be presented by visit for each treatment arm 
 
11 
Interim Study Report 
Data will be provided to DSMB (constituted prior to first patient screened) on a periodic basis. 
Based on DSMB recommendation, interim clinical study report may be prepared and submitted to 
DCGI/regulatory agencies. 
 
12 
Key Definitions 
For few assessments (weight, physical examination, vital signs haematology, biochemistry Chest 
X Ray/CT scan), screening assessments will be considered as baseline assessment (as day 1). 
Stable SpO2: 
 
• Stable SpO2: Defined as absence of increase in FiO2 to maintain Spo2 ≥ 92% 
• Improvement of SpO2: Defined as decrease in FiO2 to maintain SpO2 >92% 
 
Stable PaO2: 
 
• Stable PaO2: Defined as up to 10% change in PaO2/FiO2 ratio from baseline 
• Improvement of PaO2: Defined as > 10% improvement in PaO2/FiO2 ratio from baseline 
(including patients weaned off oxygen) 
 
If assessment is missing on particular day then it should be captured from assessment available in 
next two days. 
For lab parameters, if assessment is missing on particular day, then it should be captured from 
assessment available in ± 2 days. 


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13 
Programming Considerations, Listing of Tables, Figures & Format, 
Software detail 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using SAS® for 
Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA) or any other validated statistical 
software. One SAS program will be used to create several outputs / a separate SAS program will 
be created for each output. Output files will be delivered in Word / pdf format. 
For few assessments (weight, physical examination, vital signs haematology, biochemistry Chest 
X Ray/CT scan), screening assessments will be considered as baseline assessment (as day 1). 
Missing data: 
All attempts will be made to collect all data per protocol. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses may be performed to examine the impact 
of including or excluding the outliers. Subjects who meet fatal outcome during the observing 
period up to 30 days will be an event. Subjects lost to follow up or withdraw consent during the 
observing period, will be censored at last assessment. Patient data will be censored at the time of 
their last observed assessment in case of lost to follow up, withdrawal consent or after 30 days of 
enrolment. 
Following Rules may be applied for the derivation of efficacy endpoints 
• Patients who discharged from hospital (with improvement, Off O2), the status at 
discharge will be carried forward. 
• Patients who lost to follow up will be considered as Non evaluable (NE) 
• Patients who worsen or met fatal outcome, status at event will be carried forward. 
Note: Telephonic improvement of weaning of O2 will be considered as improved. 
 
These rules will be applied to analyse following endpoint: 
Proportion of patients with deterioration of lung function as measured by: 
• Stable SpO2 without increasing FiO2 
• Stable PaO2 without increasing FiO2 


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Listing of Tables, Figures & Format 
 
Table, figure, and listing shells are presented in Appendices 14. The formatting of the final version 
of a table, figure, or listing may differ from what is presented in the shell or the presentation of the 
results may be changed, however the key content will remain unchanged. Additional 
summaries/data points may be included in the final version of a table, figure, or listing, as well. 
Additional tables, figures, and listings may be generated to supplement the planned output. 
Software Detail 
SAS version 9.4 or any validated statistical software will be used to generate all tables, figures 
and listings. 
 
14 
Tables and mock shells 
 
 
14.1.1 
Screening Failures 
 
 
Overall 
N (%) 
Total Screened Subjects 
XX (XX.X %) 
Screen Failures 
XX (XX.X %) 
Total Randomized Subject 
XX (XX.X %) 
Subject met Inclusion Criteria or met Exclusion Criteria 
XX (XX.X %) 
Subject not met Inclusion Criteria or met Exclusion Criteria 
XX (XX.X %) 
Others 
XX (XX.X %) 
• 
Withdrawal Informed Consent 
XX (XX.X %) 
• 
Lost to Follow-Up 
XX (XX.X %) 
……. 
Note: XX patients could not complete first dosing hence replaced as per the protocol. 


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14.1.2 
Disposition of Patients 
 
 
Disposition 
Arm A 
[n (%)] 
Arm B 
[n (%)] 
Randomized 
XX (XX.X %) 
XX (XX.X %) 
ITT/FAS Population 
XX (XX.X %) 
XX (XX.X %) 
Safety Population 
XX (XX.X %) 
XX (XX.X %) 
Completed the study 
XX (XX.X %) 
XX (XX.X %) 
Completed 30 days follow up in hospital 
Early discharged* 
Discontinued 
XX (XX.X %) 
XX (XX.X %) 
Reasons for Discontinuation 
Adverse event 
XX (XX.X %) 
XX (XX.X %) 
Death 
XX (XX.X %) 
XX (XX.X %) 
Physician decision 
XX (XX.X %) 
XX (XX.X %) 
As per Protocol 
XX (XX.X %) 
XX (XX.X %) 
Lost to follow up 
XX (XX.X %) 
XX (XX.X %) 
Subject/Guardian decision 
XX (XX.X %) 
XX (XX.X %) 
Diagnosis of COVID 19 by RT-PCR 
Positiive 
XX (XX.X %) 
XX (XX.X %) 
Negative 
XX (XX.X %) 
XX (XX.X %) 
Not Available 
XX (XX.X %) 
XX (XX.X %) 
* Patients discharged early due to clinical improvement and government policy during the study. 


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14.1.3 
Subject Disposition by Centre 
 
 
Center Number 
Arm A 
[n (%)] 
Arm B 
[n (%)] 
1 
XX (XX.X %) 
XX (XX.X %) 
2 
XX (XX.X %) 
XX (XX.X %) 
3 
XX (XX.X %) 
XX (XX.X %) 
4 
XX (XX.X %) 
XX (XX.X %) 
 
 
14.1.4 
Summary of Demographic Characterstics 
 
 
Arm A 
[n (%)] 
Arm B 
[n (%)] 
Age (years) 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Sex, n (%) 
Male 
XX (XX.X %) 
XX (XX.X %) 
Female 
XX (XX.X %) 
XX (XX.X %) 
Race, n (%) 
Asian 
XX (XX.X %) 
XX (XX.X %) 
Black 
XX (XX.X %) 
XX (XX.X %) 
Ethnicity 
Hispanic 
XX (XX.X %) 
XX (XX.X %) 
East Asian 
XX (XX.X %) 
XX (XX.X %) 


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14.1.5 Summary of Concomitant Medication by treatment group 
 
 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Any medication taken 
Yes 
XX (XX.X %) 
XX (XX.X %) 
No 
XX (XX.X %) 
XX (XX.X %) 
ATC 
XXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXX 
XX (XX.X %) 
XX (XX.X %) 
Medication Name 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXXXXXXXX 
XX (XX.X %) 
XX (XX.X %) 
 
14.1.6 
Summary of Medical History 
 
 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Diagnosis of COVID 19 by RT-PCR Positive , n (%) 
XX (XX.X %) 
XX (XX.X %) 
Duration of COVID-19 related symptoms at enrolment 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Patients with co-morbidities 
Diabetes Mellitus 
XX (XX.X %) 
XX (XX.X %) 
Hypertension 
XX (XX.X %) 
XX (XX.X %) 
Others 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 


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14.1.7 
Summary of Vital Parameters and change from Baseline 
 
 
Variable 
Visit 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Weight (kg) 
Baseline 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
48 hours 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Change from Baseline 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
 
Note: *: repeated for Weight, Body Temperature, Pulse, Systolic, Diastolic, Respiratory Rate, PaO2/FiO2, FiO2, SpO2, Mean Arterial Pressure, 
Glasgow Coma Scale, PaO2 etc 
# Repeated for Day 7, Day 14, Day 21, Day 30 and EOS 


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14.1.8 
Summary of Laboratory Test Results and Change from Baseline: 
Hematology 
 
 
Test 
Visit 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Haematocrit* % 
Baseline& 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Day 7 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Change from Baseline&& 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
 
&: Repeat for day 14, Day 21, 30/EOS for all applicable parameters, 
&&: Repeat for Day 14, Day 21, Day 30/EOS Change from Baseline 
*: Haemoglobin, Total leukocyte count, Platelet count, Absolute lymphocyte count, Absolute neutrophil count, Basophils- Differential, 
Eosinophils- Differential, Lymphocytes- Differential, Monocytes- Differential and Neutrophils- Differential.etc 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.9 
Summary of Laboratory Test Results and Change from Baseline: 
Biochemistry 


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Variable 
Time point 
Visit 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Blood Urea* 
Predose 
Baseline& 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
12-24 hours 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Change from Baseline 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
12-24Hrs Post 
Dose 
Day 7&& 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
 
&: Repeat for day 14, Day 21, 30/EOS for all applicable parameters , Change from Baseline, Week 3, Change from Baseline, Week 4 and Change 
from Baseline 
&&: Repeat for Day 14, Day 21, Day30/EOS 2, Change from Baseline, 
 
*: Serum Bilirubin, AST (SGOT), ALT (SGPT), ALP, Serum Albumin, LDH, HDL, LDL, Triglycerides, Total Cholesterol, Serum creatinine, 
Procalcitonin, d-Dimer, Trop-I, Ferritin etc. 


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14.1.10 Hospitalization 
 
 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Was patient hospitalized during study? 
Yes 
XX (XX.X %) 
XX (XX.X %) 
No 
XX (XX.X %) 
XX (XX.X %) 
Discharged During study 
Yes 
XX (XX.X %) 
XX (XX.X %) 
No 
XX (XX.X %) 
XX (XX.X %) 
N/A 
XX (XX.X %) 
XX (XX.X %) 
Was patient in Intensive Care Unit during this hospitalization period 
Yes 
XX (XX.X %) 
XX (XX.X %) 
No 
XX (XX.X %) 
XX (XX.X %) 


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14.1.11 Duration of hospitalization and ICU stay 
 
 
Arm A 
[n (%)] 
Arm B 
[n (%)] 
No of days of hospitalization 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
No of days of hospitalization during study 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
No of days of ICU 
N 
Xxx 
Xxx 
Mean (SD) 
Xxx 
Xxx 
Median 
Xxx 
Xxx 
Min, Max 
Xxx 
Xxx 
No of days of ICU during study 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Time to independence from non-invasive mechanical ventilation calculated in days 
N 
Xxx 
Xxx 
Mean 
Xxx 
Xxx 
Median 
Xxx 
Xxx 
Min, Max 
Xxx 
Xxx 
Duration in Days for independence from oxygen therapy 
N 
Xxx 
Xxx 
Mean 
Xxx 
Xxx 
Median 
xxx 
Xxx 
Min, Max 
xxx 
Xxx 


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14.1.12 Summary of Study Treatment: Itolizumab treatment details in Arm 
A 
Arm A 
Dose 
N 
XX 
Mean (SD) 
XX.X (XX.XX) 
Median 
XX.X 
Min, Max 
XX, XX 
No of infusion received during study 
1 
XX (XX.X %) 
2 
XX (XX.X %) 
3 
XX (XX.X %) 
4 
XX (XX.X %) 
Infusion interrupted 
Yes 
XX (XX.X %) 
No 
XX (XX.X %) 
Reason for interruption 
XXXX 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
Regimen administered 
Weekly 
XX (XX.X %) 
Alternate weekly 
XX (XX.X %) 
Dose deferred 
Yes 
XX (XX.X %) 
No 
XX (XX.X %) 
Reason 
XXXX 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XXXX 
XX (XX.X %) 


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14.1.13 Summary of BSC treatment details in both arms 
 
Arm A 
n (%) 
Arm B 
n (%) 
Antibiotics 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
Antivirals 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
HCQ 
XX (XX.X %) 
XX (XX.X %) 
Heparin 
XX (XX.X %) 
XX (XX.X %) 
Glucocorticoids 
Supplements 
XX (XX.X %) 
XX (XX.X %) 
IV fluids 
XX (XX.X %) 
XX (XX.X %) 
Others 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 
XXXX 
XX (XX.X %) 
XX (XX.X %) 


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14.2 Primary outcome measures 
 
14.2.1 Primary Outcome Measures 
 
Visit* 
Arm A 
(N=XX) 
Arm B (N=XX) 
Baseline 
patients with Stable SpO2 without increasing FiO2 
XX (XX.X %) 
XX (XX.X %) 
patients with Stable PaO2 without increasing FiO2 
XX (XX.X %) 
XX (XX.X %) 
*day 7, day 14, day 21 and day 30/EOS or all available visits 
 
 
 
14.2.2 Proportion of patients needed intubation during the study 
 
 
Arm A 
(N=XX) 
Arm B (N=XX) 
Patients needed intubation n(%) 
XX (XX.X %) 
XX (XX.X %) 
 
 
14.2.3 Reduction in proportion of patients who need Non-invasive ventilation 
 
 
Visit 
Arm A 
(N=XX) 
Arm B (N=XX) 
Patients on Non-invasive ventilation at baseline 
XX 
XX 
Day 7 
N 
XX 
XX 
Stable or improved (shifted to bag and mask, NRBM, FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 14 
N 
XX 
XX 
Stable or improved (shifted to bag and mask, NRBM, FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 21 
N 
XX 
XX 
Stable or improved (shifted to bag and mask, NRBM, FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 30/EOS 
N 
XX 
XX 
Stable or improved (shifted to bag and mask, NRBM, FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 


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14.2.4 Reduction in proportion of patients who need NRBM 
 
Visit 
Arm A 
(N=XX) 
Arm B (N=XX) 
Patients on NRBM at baseline 
XX 
XX 
Day 7 
N 
XX 
XX 
Stable or improved (shifted to FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 14 
N 
XX 
XX 
Stable or improved (shifted to FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 21 
N 
XX 
XX 
Stable or improved (shifted to FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 30/EOS 
N 
XX 
XX 
Stable or improved (shifted to FM, nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
 
 
14.2.5 Reduction in proportion of patients who need Face Mask 
 
 
Visit 
Arm A 
(N=XX) 
Arm B (N=XX) 
Patients on FM at baseline 
XX 
XX 
Day 7 
N 
XX 
XX 
Stable or improved (shifted to nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 14 
N 
XX 
XX 
Stable or improved (shifted to nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 21 
N 
XX 
XX 
Stable or improved (shifted to nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 30/EOS 
N 
XX 
XX 
Stable or improved (shifted to nasal canula or off O2) 
XX (XX.X %) 
XX (XX.X %) 


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14.2.6 Reduction in proportion of patients who need High Flow Nasal Oxygen 
 
 
Visit 
Arm A 
(N=XX) 
Arm B (N=XX) 
Patients on High flow nasal oxygen at baseline 
XX 
XX 
Day 7 
N 
XX 
XX 
Stable or improved (off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 14 
N 
XX 
XX 
Stable or improved (off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 21 
N 
XX 
XX 
Stable or improved (off O2) 
XX (XX.X %) 
XX (XX.X %) 
Day 30/EOS 
N 
XX 
XX 
Stable or improved (off O2) 
XX (XX.X %) 
XX (XX.X %) 
 
 
14.2.7 One-month Mortality Rate 
 
 
Arm A 
[n (%)] 
Arm B 
[n (%)] 
Number of patients died 
XX (XX.X %) 
XX (XX.X %) 
95% CI Difference between Rate 
XX (XX , XX) 
p-value 
XX 
 
14.2.8 Change in inflammatory markers before and after dosing in 
Treatment ARM A 
 
 
Before dose 
12-24 hrs after dosing 
Serum ferritin 
First dose (n) 
Mean change 
Second dose (n) 
Mean change 
Third Dose (n) 
Mean change 
Fourth Dose (n) 
Mean change 
Programming Note: Repeat for other inflammatory markers: Serum LDH, Serum CRP, Serum d-Dimer etc 
Repeat Table for first , second, third and fourth infusion (dose) of Itolizumab 


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14.2.9 Survival status 
Arm A 
(N=XX) 
[n (%)] 
Arm A 
(N=XX) 
[n (%)] 
Survival Status 
XX (XX.X %) 
XX (XX.X %) 
Alive 
XX (XX.X %) 
XX (XX.X %) 
Dead 
XX (XX.X %) 
XX (XX.X %) 
Unknown 
XX (XX.X %) 
XX (XX.X %) 
 
14.2.10 Summary of Oxygen and SOFA analysis 
 
 
Variable 
Arm A 
(N=XX) 
[n (%)] 
Arm B 
(N=XX) 
[n (%)] 
Oxygen requirement (L/min) 
Week 1* 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Week2 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Change from Week 1 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
SOFA score 
Week 1* 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Week2 
N 
XX 
XX 
Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
Change from Week 1 
N 
XX 
XX 


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Mean (SD) 
XX.X (XX.XX) 
XX.X (XX.XX) 
Median 
XX.X 
XX.X 
Min, Max 
XX, XX 
XX, XX 
*Repeated for Day 7, day 14, day 21 and Day 30/EOS 
 
14.2.11 Ordinal Scale: No and Proportion of patient reduced by 1 or more 
points 
 
 
Day 7 
n (%) 
Day 14 
n (%) 
Day 21 
n (%) 
Day 30/EOS 
n (%) 
Arm A 
(n=XX) 
Arm B 
(n=XX) 
 
 
14.2.12 Respiratory rate over time 
 
 
Sr. No. 
Arm A (N=xx) 
Arm B (N=xx) 
Up to 20 
> 20 
Up to 20 
> 20 
Baseline 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Day 2/3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Day 7 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Day 14 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Day 21 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Day 30/EOS 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 


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14.3 Safety Analysis 
 
14.3.1 Summary of Subjects with TEAEs by treatment group 
 
 
 
Description 
ARM A 
(N=XX) 
[n (%)] 
No of events 
ARM B 
(N=XX) 
[n (%)] 
No of events 
At least one TEAE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one related TE AE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one Severe/Grade 3 or above TEAE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one related Severe/Grade 3 or above TE AE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one IRR 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one TE SAE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
At least one related TE SAE 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Fatal TEAEs 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Fatal AE related to study drug 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Number of patients with dose temporarily stopped at least 
once 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Number with dose permanently stopped 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Seriousness criteria 
XX 
XX 
Death 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Life threatening 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Requires in-patient hospitalization or prolongation of 
existing hospitalization 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Significant disability 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Congenital anomaly or birth defect Other medically 
important serious event 
XX (XX.X %) 
XX 
XX (XX.X %) 
XX 
Note1 : TEAE are defined as any AE which started or deteriorated at or after first dose of study treatment 
Note2: Includes related AE. 
Note 3: n=number of subjects with AEs. Percentages are based on the number of subjects in safety population (N). 


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14.3.2 Treatment Emergent Adverse Event (TEAE) by SOC and PT 
 
 
System Organ Class 
Preferred term 
ARM A 
(N=XX) 
[n (%)] 
ARM B 
(N=XX) 
[n (%)] 
No of Subjects with at least one TEAE 
XX (XX.X %) 
XX (XX.X %) 
Any SOC 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
SOC1 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
PT3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
TEAE are defined as any AE which started or deteriorated at or after first dose of study treatment 
n=number of subjects with AEs. e=number of events. Percentages are based on the number of subjects in safety population 
Note: System Organ Class and Preferred Term coded as per MedDRA version XX 


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14.3.3 Treatment Emergent Adverse Event (TEAE) by severity 
 
 
 
System 
Organ Class 
Preferred 
term 
ARM A 
(N=XX) 
[n (%)] 
ARM B 
(N=XX) 
[n (%)] 
Mild 
Moderate 
Severe 
Life 
threatening 
Death 
Mild 
Moderate 
Severe 
Life 
threatening 
Death 
 
Any SOC 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
PT1 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
PT2 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
SOC1 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
PT1 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
PT2 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
PT3 
XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) XX (XX.X %) 
 
 
 
 
14.3.4 Treatment Emergent Adverse Event (TEAE) related to study drug 
 
System Organ Class 
Preferred term 
ARM A 
(N=XX) 
[n (%)] 
ARM B 
(N=XX) 
[n (%)] 
Related 
Not related 
Related 
Not related 
Any SOC 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
SOC1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Note: System Organ Class and Preferred Term coded as per MedDRA version XX 
 
 
14.3.5 Treatment Emergent Adverse Event (TEAE) by Outcome 
 
 
ARM 
System Organ 
Class 
Preferred 
term 
Recovered/resolved Recovering/resolving 
Not recovered/not 
resolved 
Recovered/resolved 
with sequelae 
Fatal 
Unknown 


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Arm A (N=XX) Any SOC 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
SOC1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
Arm B (N=XX) Any SOC 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
SOC1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT1 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT2 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
PT3 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
XX (XX.X %) 
 
15. Supplementary Tables 
 
Table S1: Mean Lymphocyte count 
 
Baseline 
Day 2/3 
Day 7 
Day 14 
Day 21 
Day 30/EOS 
n 
Arm A 
Arm B 
 
Table S2: Mean PaO2/FiO2 ratio 
 
Baseline 
Day 2/3 
Day 7 
Day 14 
Day 21 
Day 30/EOS 
n 
Arm A 
Arm B 
 
Table S3: Mean PaO2 / FiO2 ratio in Arm A 
 
Before dose 
48 hrs after dose 
First dose (n) 
PaO2 / FiO2 ratio 
Mean change 
Second dose (n) 
PaO2 / FiO2 ratio 
Mean change 
Third dose (n) 
PaO2 / FiO2 ratio 
Mean change 
Fourth dose (n) 


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PaO2 / FiO2 ratio 
Mean change 
 
 
 
Table S4: Mean PaO2 
 
Baseline 
Day 2/3 
Day 7 
Day 14 
Day 21 
Day 30/EOS 
Arm A 
Arm B 
 
Table S5: Mean FiO2 (%) 
 
Baseline 
Day 2/3 
Day 7 
Day 14 
Day 21 
Day 30/EOS 
Arm A 
Arm B 
 
Table S6: Mean SpO2 (%) 
 
Baseline 
Day 2/3 
Day 7 
Day 14 
Day 21 
Day 30/EOS 
Arm A 
Arm B 
 
 
16. Listings 
 
Listing 16.1.1 Subjects Inclusion 
 
Treatment 
Group 
Subje 
ct ID 
Is the subject eligible for study enrolment based on satisfying all 
inclusion and exclusion criteria requirement? 
IN 
C 1 
IN 
C 2 
IN 
C 3 
IN 
C 4 
IN 
C 5 
IN 
C 6 
IN 
C 7 
XXXXX 
X 
XXX 
XXXX 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XXXXX 
X 
XXX 
XXXX 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
XX 
X 
 
Listing 16.1.2 Subjects Exclusion 
 
Treatment 
Group 
Subject 
ID 
Is the subject 
eligible for 
study 
enrolment 
based on 
satisfying all 
inclusion and 
exclusion 
criteria 
requirement? 
EXC 1 
EXC 2 
EXC 3 
EXC 4 
EXC 5 
EXC 6 
EXC 7 
EXC 8 
EXC 9 
EXC 
10 
EXC 11 
EXC 
12 


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XXXXXX 
XXX 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
Listing 16.1.3 Demographic data 
 
 
Treatment Group 
Subject 
ID 
Age 
Was written informed 
consent obtained? 
Date of Informed 
Consent 
Gender 
Date of 
birth 
Is subject of child 
bearing status 
Race 
Ethnicity 
XXXXXX 
XXX 
XX 
XXX 
XXX 
XXXX 
XXXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XX 
XXX 
XXX 
XXXX 
XXXX 
XXX 
XXX 
XXX 
 
Listing 16.1.4 Medical History 
 
 
Treatment 
Group 
Subject 
ID 
Diagnosis of 
COVID 19 by RT- 
PCR 
Date 
Result 
Is there any 
Medical History to 
be reported 
Serial 
Number 
Medical 
history term 
Start 
Date 
Stop Date 
Ongoing 
XXXXXX 
XXX 
XX 
XXXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XX 
XXXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Listing 16.1.5 Concomitant Medication 
 
 
Treatment 
Group 
Subject 
ID 
Were any 
medication(s) 
taken? 
Medication 
Name 
Indication 
Start 
Date 
End 
Date 
Ongoing 
at final 
exam 
Frequency 
Route 
Dose 
Dose 
units 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 
XX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 
XX 
XXX 
 
Listing 16.1.6 Disposition of Subjects 
 
 
Treatment 
Group 
Subject 
ID 
Is the subject 
eligible to 
participate in 
treatment 
phase? 
Did the 
subject 
complete 
study? 
If No, primary 
reason for 
discontinuation 
Date of 
last 
contact 
Date of 
consent 
withdrawn 
Diagnosis 
of COVID 
19 by RT- 
PCR 
Date 
Result 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 


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Listing 16.1.7 Vital Parameters 
 
 
Treatm 
ent 
Group 
Subj 
ect 
ID 
Date of 
assessm 
ent 
Time of 
assessm 
ent 
V 
isi 
t 
Was 
assessment 
performed? 
He 
ig 
ht 
W 
eig 
ht 
Body 
Tem 
pe 
ratur 
e 
P 
ul 
se 
Blood 
Pressu 
re 
Resp 
irato 
ry 
Rate 
Pa 
O 
2 
/F 
iO 
2 
Fi 
O 
2 
S 
p 
O 
2 
M 
A 
P 
G 
C 
S 
P 
a 
O 
2 
XXXX 
XX 
XX 
X 
XXXX 
XX 
X 
X 
X 
XXXX 
X 
X 
X 
X 
X 
XXX 
X 
X 
X 
XXX 
XX 
X 
X 
X. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XXXX 
XX 
XX 
X 
XXXX 
XX 
X 
X 
X 
XXXX 
X 
X 
X 
X 
X 
XXX 
X 
X 
X 
XXX 
XX 
X 
X 
X. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Listing 16.1.8 Biomarker 
 
Treatment 
Group 
Subject 
ID 
Visit 
Was blood 
sample 
collected pre 
dose? 
Date of sample 
collected Pre- 
Dose 
Time of sample 
collected pre 
dose 
Was blood sample 
collected 12-24 Hours 
post dose? 
Date of sample 
collected Post- 
Dose 
Time of sample 
collected 24 
Hours post dose 
XXXXXX 
XXX 
XXX 
XXXX 
XXXX 
XX 
XXX 
XXXX 
XX 
XXXXXX 
XXX 
XXX 
XXXX 
XXXX 
XX 
XXX 
XXXX 
XX 
 
 
Listing 16.1.9 Haematology 
 
 
Tre 
atm 
ent 
Gro 
up 
Su 
bj 
ec 
t 
ID 
V 
i 
s 
i 
t 
Was 
blood 
sample 
collected 
pre dose 
Date of 
sample 
collecte 
d Pre- 
Dose 
Time of 
sample 
collecte 
d pre 
dose 
Was blood 
sample 
collected 
12 Hours 
post dose 
Date of 
Sample 
collecte 
d Post 
dose 
Time of 
sample 
collected 
12 Hours 
post 
Tes 
t 
Par 
am 
eter 
Res 
ult- 
PRE 
- 
DO 
SE 
Result 
- 
12Hrs 
POST 
DOSE 
Lowe 
r 
Refer 
ence 
Rang 
e 
Uppe 
r 
Refer 
ence 
Rang 
e 
U 
ni 
t 
(S 
I) 
XX 
XX 
XX 
X 
X 
X 
X 
X 
X 
XXX 
XXXX 
XX 
XXX 
XXXX 
XX 
XX 
XX 
X 
XX 
X 
XXX 
XXX 
XXX 
X 
X 
XX 
XX 
XX 
X 
X 
X 
X 
X 
X 
XXX 
XXXX 
XX 
XXX 
XXXX 
XX 
XX 
XX 
X 
XX 
X 
XXX 
XXX 
XXX 
X 
X 
Note: provide the listing for Haematology parameters as per available data 
 
 
Listing 16.1.10 Biochemistry 
 
 
 
Treatment 
Group 
Subject 
ID 
Visit 
Was 
blood 
sample 
collected 
pre dose 
Date of 
sample 
collected 
Pre- 
Dose 
Time of 
sample 
collected 
pre dose 
Was 
blood 
sample 
collected 
12 
Hours 
Date of 
Sample 
collected 
Post 
dose 
Time of 
sample 
collected 
12 
Hours 
post 
Test 
Parameter 
Result- 
PRE- 
DOSE 
Result- 
12Hrs 
POST 
DOSE 
Lower 
Reference 
Range 
Upper 
Reference 
Range 
Unit 
(SI) 


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post 
dose 
XXXXXX 
XXX 
XXX 
XXX 
XXXX 
XX 
XXX 
XXXX 
XX 
XXXXX 
XXX 
XXX 
XXX 
XXX 
XX 
XXXXXX 
XXX 
XXX 
XXX 
XXXX 
XX 
XXX 
XXXX 
XX 
XXXXX 
XXX 
XXX 
XXX 
XXX 
XX 
Note: provide the listing for Haematology parameters as per available data 
 
 
 
Listing 16.1.11 Study Treatment - Itolizumab 
 
 
 
 
 
 
 
 
Listing 16.1.12 Study Treatment - Supportive Care/Oxygen Therapy 
 
Tr 
ea 
tm 
en 
t 
Gr 
ou 
p 
S 
u 
b 
j 
e 
c 
t 
I 
D 
Na 
m 
e 
of 
tre 
at 
m 
en 
t 
St 
art 
da 
te 
of 
D 
os 
e 
En 
d 
da 
te 
of 
D 
os 
e 
D 
o 
s 
e 
F 
r 
e 
q 
u 
e 
n 
c 
y 
R 
o 
u 
t 
e 
S 
t 
a 
r 
t 
T 
i 
m 
e 
o 
f 
i 
n 
f 
u 
s 
i 
o 
n 
Wa 
s 
infu 
sio 
n 
inte 
rru 
pte 
d 
Reas 
on 
for 
infus 
ion 
inter 
rupti 
on 
Stop 
time 
of 
infus 
ion 
interr 
uptio 
n 
Res 
tart 
Ti 
me 
of 
inf 
usi 
on 
Deli 
very 
mod 
e for 
inha 
latio 
n 
Da 
te 
of 
int 
ub 
ati 
on 
Sta 
rt 
Ti 
me 
of 
intu 
bati 
on 
Da 
te 
of 
ex 
tu 
ba 
tio 
n 
Sta 
rt 
Ti 
me 
of 
ext 
uba 
tion 
Was 
weanin 
g from 
mechan 
ical 
ventilat 
ion 
done? 
D 
at 
e 
of 
w 
ea 
ni 
ng 
Ti 
m 
e 
of 
w 
ea 
ni 
ng 
Re 
as 
on 
for 
ch 
an 
ge 
S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XX 
XX 
XXX 
X 
XX 
XX 
XX 
XX 
X 
X 
X 
X 
XX 
XX 
X 
X 
X 
X 
XX 
XX 
XXXX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
X 
XX 
XX 
XXX 
X 
XX 
XX 
XX 
XX 
X 
X 
X 
X 
XX 
XX 
X 
X 
X 
X 
XX 
XX 
XXXX 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Group 
Subject 
ID 
Date 
of 
dose 
Dose 
Frequency 
Route 
Start 
Time of 
infusion 
End 
Time of 
infusion 
Was 
Infusion 
interrupted? 
Reason for 
infusion 
interruption 
Stop Time 
of infusion 
interruption 
Restart 
Time of 
infusion 
Type 
of 
change 
Reason 
for 
change 
Was 
premedication
Hydrocortison
administered?
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 
XXXX 
XXXX 
XXXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 
XXXX 
XXXX 
XXXX 


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Listing 16.1.13 Chest X Ray/CT Scan 
 
 
Treatment 
Group 
Subject ID 
Was CHEST X 
RAY 
performed? 
Date of 
assessment 
CHEST X 
RAY 
comments 
CT SCAN 
comments 
XXXXXX 
XXX 
XXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
 
 
Listing 16.1.14 Adverse Event (Part1) 
 
Treatment 
Group 
Subject 
ID 
Were any 
adverse 
events 
reported? 
Adverse 
event 
number 
Adverse 
event 
term 
Does this 
AE meet 
definition 
of SAE? 
Seriousness 
criteria 
Severity 
of event 
as per 
CTCAE 
ver 4.03 
Reasonable 
possibility 
that AE 
related to 
Study Drug 
Start 
Date 
End date 
XXXXXX 
XXX 
XXX 
XXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
 
Listing 16.1.15 Adverse Event (Part-2) 
 
 
Is it a 
Was any 
Treatment 
Group 
Subject 
ID 
study drug 
infusion 
site 
Relationship 
to study drug 
If “Unlikely/Unrelated” 
to study drug, 
alternative etiology 
Action 
taken on 
Study 
Did this AE lead 
to 
discontinuation 
concomitant 
medication 
taken for this 
reaction? 
Drug 
from the study 
AE? 
Outcome 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Listing 16.1.16 Hospitalization 
 
 
 
 
 
Treatment 
Group 
Subject 
ID 
Was patient 
hospitalized 
during 
study? 
Date of 
Admission 
Date of 
Discharge 
Ongoing at 
final 
examination 
Was patient in 
Intensive Care 
Unit during 
this 
hospitalization 
period 
Date of 
admission 
to ICU 
Date of 
discharge 
from 
ICU 
If yes, 
number 
of days 
in 
Intensive 
care unit 
Primary 
reason for 
hospitalization 
Were these 
additional organ 
support needed? 
 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXX 
XXXX 


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Listing 16.1.17 Survival Status 
 
 
Treatment Group 
Subject ID 
Date of assessment 
Survival Status 
Last known 
date subject 
alive 
If Subject died, 
kindly record- 
Date of Death 
Time of death 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Listing 16.1.18 SOFA Score 
 
 
Treatment 
Group 
Subject 
ID 
Respiratory 
system 
(PaO2/FiO2) 
Central 
Nervous 
system 
(Glasgow 
Coma Scale) 
Cardiovascular system 
(Mean arterial pressure 
(MAP) OR 
administration 
of 
vasopressors required) 
Liver 
(Bilirubin 
(mg/dl) 
[μmol/L]) 
Coagulation 
(Platelets ×103/ml) 
Kidney 
(Creatinine 
(mg/dl) 
[μmol/L]; urine 
output) 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
Listing 16.1.19 Ordinal Scale 
 
Treatment Group 
Subject ID 
Patient state 
Descriptor 
Score 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
XXX 
XXX 
XXX 
XXX 
Graphs 
 
• Figure 1: Disposition by centres: Bar Graph 
 
• Figure 2: PaO2/FiO2 ratio: Line Graph 
 
• Figure 3: change from baseline for Key Lab parameters: Ferrtin, d-dimer, LDH, CRP, 
Lymphocyte counts 
 
• Figure 4: KM Curve for time to event endpoints