Clinical Trials Register

Summary
EudraCT Number:	2020-003278-37
Sponsor's Protocol Code Number:	INSIGHT014
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-08-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2020-003278-37

A.3

Full title of the trial

A Multicentre, Adaptive, Randomised, Blinded Controlled Trial
of the Safety and Efficacy of Investigational Therapeutics
for Hospitalised Patients with COVID-19

Short Title: Therapeutics for Inpatients with COVID-19 (TICO)

INSIGHT Protocol Number: 014 / ACTIV-3

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Therapeutics for Inpatients with COVID-19 (TICO)

A.3.2

Name or abbreviated title of the trial where available

Therapeutics for Inpatients with COVID-19 (TICO)

A.4.1

Sponsor's protocol code number

INSIGHT014

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04501978

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Reagents of the University of Minnesota
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MRC CTU at UCL
B.5.2	Functional name of contact point	Sarah Pett
B.5.3	Address:
B.5.3.1	Street Address	90 High Holborn
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC1V 6LJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02076704700
B.5.5	Fax number	02076704818
B.5.6	E-mail	s.pett@ucl.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LY3819253
D.3.2	Product code	SUB127300
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LY3819253
D.3.9.4	EV Substance Code	AS2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Synthetically made product, modelled from a human antibody
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Remdesivir
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Remdesivir
D.3.2	Product code	SUB195655
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Remdesivir (active drug Triphosphate)
D.3.9.1	CAS number	1809249-37-3
D.3.9.2	Current sponsor code	GS-5734
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	Conc nos=5mg/mL
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

E.1.1.1

Medical condition in easily understood language

COVID-19

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	PT
E.1.2	Classification code	10051905
E.1.2	Term	Coronavirus infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary endpoint of TICO is to test whether the nMAb(s) result in more people with ‘sustained’ recovery i.e. discharged from hospital, alive, and home for 14 consecutive days by Day 90.

E.2.2

Secondary objectives of the trial

1) For everyone enrolled during stage 1 and 2 of the trial the secondary research questions are to define, the numbers of deaths through 90 days of follow-up; the number of people who experience sustained recovery over 90 days, the time to discharge from the initial hospital, and the number of days alive up to day 90.

2) Changes in the scores to assess people’s lung and respiratory function on Days 1-7, and Days 14 and 28.

3) Changes between Day 0 and Day 5 in the National Early Warning (NEW) score, this is a scoring system validated in the UK, which is able to score how sick people are, and their risk of dying, based on things like their blood pressure, pulse rate and body temperature.

4) Clinical organ failure defined by development of any one or more of the following through Day 28

a. Respiratory system dysfunction including the need for oxygen therapy or ventilation
b. Cardiac problems include heart attacks and heart failure
c. Low blood pressure requiring drug support to mai

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

INSIGHT Genomics Study (Protocol No. 004 version 2.0, dated 27 August 2013)
The purposed of this study is to obtain a whole blood sample from which DNA will be extracted to study polymorphisms in immune response genes and other genetic variants that may be associated with an increased risk of disease progression among individuals with infectious diseases of public health importance who are enrolled in qualifying INSIGHT studies.

E.3

Principal inclusion criteria

1. Age ≥ 18 years;

2. Informed consent by the patient or the patient’s legally-authorized representative (LAR)*

3. SARS-CoV-2 infection, documented by PCR or other nucleic acid test (NAT) within 3 days prior to randomization OR documented by NAT more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection per the responsible investigator;

4. Duration of symptoms attributable to COVID-19 ≤ 12 days per the responsible investigator;

5. Requiring admission for inpatient hospital acute medical care for clinical manifestations of COVID-19, per the responsible investigator, and NOT for purely public health or quarantine purposes.

*Continuing consent
Participants for whom consent was initially obtained from a LAR, but who subsequently regain decision-making capacity while in hospital will be approached for consent for continuing participation, including continuance of data collection.

E.4

Principal exclusion criteria

1. Prior receipt of any SARS-CoV-2 hIVIG, convalescent plasma from a person who recovered from COVID-19 or any SARS-CoV-2 nMAb at any time prior to hospitalization;

2. Not willing to abstain from participation in other COVID-19 treatment trials until after Day 5;

3. In the opinion of the responsible investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol-specified assessments;

4. Expected inability to participate in study procedures;

5. Women of child-bearing potential who are not already pregnant at study entry and who are unwilling to abstain from sexual intercourse with men or practice appropriate contraception through Day 90 of the study.

6. Men who are unwilling to abstain from sexual intercourse with women of child-bearing potential or who are unwilling to use barrier contraception through Day 90 of the study.

7. stage 1 only]
Presence at enrollment of any of the following:
a. stroke
b. meningitis
c. encephalitis
d. myelitis
e. myocardial infarction
f. myocarditis
g. pericarditis
h. symptomatic congestive heart failure (NYHA class III-IV)
i. arterial or deep venous thrombosis or pulmonary embolism

8. stage 1 only
Current or imminent requirement for any of the following:
a. invasive mechanical ventilation
b. ECMO
c. mechanical circulatory support
d. vasopressor therapy
e. commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy).

E.5 End points

E.5.1

Primary end point(s)

Stage 1 Outcomes to Evaluate Activity
Two intermediate, ordinal categorical outcomes assessed at Day 5 are used to evaluate potential activity.
are used in stage 1. Both are ordinal categorical outcomes assessed 5 days after randomisation (Day 5); the participant’s highest (i.e. most severe) observed score on Day 5 is used.
A)“pulmonary” ordinal outcome, (7 categories) are primarily defined based on oxygen requirements.
1.Can independently undertake usual activities with minimal or no symptoms
2.Symptomatic and currently unable to independently undertake usual activities but no need of supplemental oxygen (or not above premorbid requirements)
3.Supplemental oxygen (<4 litres/min, or <4 litres/min above premorbid requirements)
4.Supplemental oxygen (≥4 litres/min, or ≥4 litres/min above premorbid requirements, but not high-flow oxygen)
5.Non-invasive ventilation or high-flow oxygen
6.Invasive ventilation, extracorporeal membrane oxygenation (ECMO), mechanical circulatory support, or new receipt of renal replacement therapy
7.Death

B)“pulmonary+, ordinal outcome ( 7 categories), captures extrapulmonary complications as well as respiratory dysfunction.
1.Can independently undertake usual activities with minimal or no symptoms
2.Symptomatic and currently unable to independently undertake usual activities but no need of supplemental oxygen (or not above premorbid requirements)
3.Supplemental oxygen (<4 litres/min, or <4 litres/min above premorbid requirements)
4.Supplemental oxygen (≥4 litres/min, or ≥4 litres/min above premorbid requirements, but not high-flow oxygen) or any of the following: stroke (NIH Stroke Scale [NIHSS] ≤14), meningitis, encephalitis, myelitis, myocardial infarction, myocarditis, pericarditis, new onset CHF NYHA class III or IV or worsening to class III or IV, arterial or deep venous thromboembolic events.
5.Non-invasive ventilation or high-flow oxygen, or signs and symptoms of an acute stroke (NIHSS >14)
6.Invasive ventilation, ECMO or mechanical circulatory support; vasopressor therapy; or new receipt of renal replacement therapy
7.Death

Stage 2 Outcomes to Evaluate Efficacy and Safety
The primary endpoint is time from randomisation to sustained recovery, defined as being discharged from the index hospitalisation, followed by being alive and home for 14 consecutive days prior to Day 90.
Home is defined as the level of residence or facility where the participant was residing prior to hospital admission leading to enrolment in this protocol.

E.5.1.1

Timepoint(s) of evaluation of this end point

Stage 1
Two intermediate outcomes to evaluate potential activity are used in
stage 1. Both are ordinal categorical outcomes assessed 5 days after
randomisation (Day 5); the participant's highest (i.e. most severe)
observed score on Day 5 is used.
Stage 2
The primary outcome is assessed during 90 days of follow-up, which is
longer than for other trials for COVID-19, which are typically 28 days.
The longer follow-up will allow better ascertainment of recovery from
the longer-term consequences of the underlying disease, and hence the
efficacy of the investigational agent. This is likely to be particularly true
for patients who experience extra-pulmonary disease in conjunction with
their COVID-19, and for patients enrolled while receiving care for life threatening
organ failure.

E.5.2

Secondary end point(s)

Several secondary efficacy endpoints will be assessed. These endpoints
will be assessed for participants enrolled during both stages of the trial.
1. All-cause mortality through 90 days of follow-up
2. Composite of time to sustained recovery and mortality through 90
days of follow-up
3. Time to discharge for the initial hospitalisation
4. Days alive outside of a short-term acute care hospital up to day 90
5. Ordinal outcomes, pulmonary+ and pulmonary, on Days 1-7, and
pulmonary ordinal outcome on Days 14 and 28
6. Change in National Early Warning (NEW) score from baseline to Day 5
7. Clinical organ failure defined by development of any one or more of
the following clinical events through Day 28:
a. Respiratory dysfunction:
b. Cardiac and vascular dysfunction:
c. Renal dysfunction:
d. Hepatic dysfunction:
e. Neurological dysfunction
f. Haematological dysfunction
g. Serious infection:
8. A composite of death or clinical organ failure COVID-19-related events (see above)
9. Outcomes assessed in other treatment trials of COVID-19 for
hospitalised participants in order to facilitate cross-trial comparisons
and overviews (e.g. 6- , 7-, and 8-category ordinal scales assessed at
Days 1-7, 14 and 28; time to improvement in 1 or 2 categories of ordinal
scale; time to best 3 categories of ordinal scale, and binary outcomes
defined by improvement or worsening based on other ordinal outcomes)
10. A composite of cardiovascular events (outcomes listed above in
items 7)
11. Safety and tolerability as measured by:
a. A composite of grade 3 and 4 clinical adverse events, SAEs, or death
through Day 5 (primary safety endpoint) and through Day 28
b. Infusion-related reactions of any severity and percentage of
participants for whom the infusion was interrupted or stopped prior to
completion
c. A composite of SAEs or death through Day 90
d. Adverse events of any grade through Day 7
e. Prevalence of adverse events of any grade at day 14 and day 28
12. Change in antibody profile, overall titres of antibodies and
neutralising antibody levels from baseline to Days 1, 3, 5 and 28 and 90

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints for the measurements are described in connection with the
individual secondary endpoints.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Adaptive

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Brazil

Denmark

France

Georgia

Germany

Greece

Ireland

Italy

Mexico

Peru

Poland

Portugal

Singapore

Spain

Sweden

Switzerland

Uganda

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1