Clinical trial NCT04473053: DEFINE - Evaluating Therapies for COVID-19
Official title: DEFINE - Evaluating Therapies for COVID-19
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: COVID-19
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: Latus Therapeutics
name: Scottish National Blood Transfusion Service (SNBTS)
First posted: 2020-07-16
Enrollment: 200
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised clinical trial - currently two treatment arms and one standard of care arm. More assets will be added to the protocol as evidence emerges.
Primary purpose: TREATMENT

Brief summary: COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus, SARS CoV2 and is a serious condition with high mortality in hospitalised patients, for which there is no currently approved treatment other than supportive care. Urgent investigation of potential treatments for this condition is required.

This protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients receiving normal standard of care.

Given the spectrum of clinical disease, community based infected patients or hospitalised patients can be included. Products requiring parenteral administration will only be investigated in hospitalised patients. Patients will be divided into cohorts, a) community b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The relevant cohort(s) for any given therapy will be detailed in the therapy-specific appendix.

Candidate therapies can be added to the protocol and previous candidates removed from further investigation as evidence emerges. The trial will be monitored by an independent Data Monitoring Committee (DMC) to ensure patient safety.

Each candidate cohort will include a small cohort of patients randomised to candidate therapy or existing standard of care management dependent on disease stage at entry. Cohort numbers will be defined in the protocol appendices.

This is a Phase IIa experimental medicine trial and as such formal sample size calculations are not appropriate.

Detailed description: This trial platform aims to support the repurposing of promising therapeutic assets with prior use in humans but without prior information on use in COVID-19, to determine the PK-PD profile of the agent, compared to standard of care supportive therapy, in small cohorts of COVID-19 patients. The results of these studies are intended to provide initial safety, pharmacokinetic and pharmacodynamic data and experimental medicine data to support further evaluation in existing national and international trial networks for candidates demonstrating appropriate impact on the dynamic marker of interest. The key interception is to mitigate the lung damage in patients with COVID-19 that leads to respiratory failure. As such, the assets in this programme will focus on abrogating putative mechanisms implicated in COVID-19 respiratory disease.

Existing approaches in clinical trials involve novel or repurposed antivirals or immunomodulatory approaches involving agents such as corticosteroids, interferon-β or hydroxychloroquine. A major limitation in the design of many early clinical trials is the limited amount of mechanistic data from patients with COVID-19. Mechanisms have been inferred from animal models, related infections or clinical syndromes. These approaches have infrequently translated to human disease. For example, remdesivir efficacy in animal models of Ebola Virus Disease (EVD) did not translate to human disease and hydroxychloroquine antiviral affects in vitro have not translated to humans against other viruses. Some drugs, such as repurposing of the anti-retroviral protease Kaletra, are still being pursued despite uncertain mechanism and despite evidence that this aspartyl protease cannot bind to the cysteine chymotrypsin-like protease that is Kaletra's putative target in COVID-19.

There is a clear and urgent need to pursue experimental medicine studies in humans to establish a solid mechanistic basis for rapid evaluation, including in existing clinical trial platforms against COVID-19 (e.g DoH RECOVERY and NIHR-CLRN industry adopted studies).

The trial will be as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges. The interim trial results will be monitored by an independent DMC to evaluate any patient safety signals.

As COVID-19 follows a variable clinical path in individual patients, the protocol is designed to enable inclusion of patients across the disease stages. The trial is intended to provide mechanistic data from patients receiving standard of care therapy and from patients treated with the therapy candidates. The study will enable delivery of pharmacokinetic information and effects of standard of care and candidate agents on surrogate biomarkers of the disease process and the specific drug target.

Eligibility criteria: Eligibility criteria for each arm is specified in the appendix and may vary depending on the intervention. As an example, eligibility criteria from the Nafamostat and TD139 arms has been provided:

Inclusion Criteria:

* Provision of informed consent from the patient or representative
* Aged at least 16 years
* If the patient is of child bearing potential, the patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study (if randomised to a treatment arm) and for at least 90 days after termination of study therapy. A vasectomised partner would be considered an appropriate birth control method provided that the partner is the sole male sexual partner and the absence of sperm has been confirmed.
* COVID-19 positive

Exclusion Criteria:

* Current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled cardiac disease (NYHA class IV), uncontrolled renal disease (eGFR \<30 mL/min/1.73 m2), severe liver dysfunction (ALT/AST \>5x ULN) or bone marrow failure (Hb \<80 g/L AND ANC\<0.5 mm3 AND platelet count \<50,000 uL)
* Women who are pregnant or breastfeeding.
* Participation in another clinical trial of an investigational medicinal product (CTIMP)
* Known hypersensitivity to the IMP or excipients (e.g. lactose)
* Pre-existing or Cconcomittant use of off-label treatments for COVID-19 that are not recognised as locally approved standard care.
* Significant electrolyte disturbance (hyperkalaemia potassium \>5.0 mmol/L or hyponatraemia sodium \< 120mmol/L)
* Patient currently receiving potassium sparing diuretics that cannot be reasonably withheld
* Patient currently receiving prophylactic or therapeutic anticoagulantsanticoagulation or antiplatelet agents that cannot be reasonably withheld if randomised to Nafamostat
* Patients (or their partners) planning on donating sperm/eggs during the trial period
* Ongoing dialysis
* History of serious liver disease (Child Pugh score \> 10)
* Hemoglobin \< 80 g/L
* Any known allergy to the IMP/excipients
* Severe uncontrolled diabetes mellitus
* In the Investigator's opinion, patient is unwilling or unable to comply with drug administration plan, laboratory tests or other study procedures.

Primary outcomes:
measure: The safety of the candidate therapies in COVID-19 patients by measuring physiological changes in the circulatory and respiratory system.
timeFrame: Up to 16 days post treatment
measure: The safety of the candidate therapies in COVID-19 patients by recording the number of treatment related adverse events.
timeFrame: Up to 90 days post treatment
Secondary outcomes:
measure: Measuring the PK of the proposed trial treatments in COVID-19 patients.
timeFrame: 6 months
measure: Measure a change in the expression of key coagulation biomarkers in the blood of COVID-19 patients during and after treatment period.
timeFrame: 6 months
measure: Measure a change in the expression of key cytokines in the blood of COVID-19 patients during and after treatment period.
timeFrame: 6 months
measure: To evaluate the improvement or deteroriation of patients in each treatment arm.
timeFrame: 16 days
measure: To evaluate the number of oxygen-free days.
timeFrame: 16 days
measure: To evaluate incidence of any form of new ventilation use.
timeFrame: 16 days
measure: To evaluate ventilator-free days
timeFrame: 16 days
measure: Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2)
timeFrame: 16 days
measure: To evaluate SARS-CoV-2 viral load.
timeFrame: 15 days
measure: To evaluate time to discharge
timeFrame: 16 days
measure: To evaluate the use of renal dialysis or haemofiltration for each treatment arm.
timeFrame: 16 days
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
Study officials:
affiliation: University of Edinburgh
name: Kev Dhaliwal
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cooper RS, Fraser AR, Smith L, Burgoyne P, Imlach SN, Jarvis LM, Turner DM, Zahra S, Turner ML, Campbell JDM. Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19. Front Immunol. 2021 Jan 8;11:598402. doi: 10.3389/fimmu.2020.598402. eCollection 2020.
citation: Gaughan E, Quinn T, Bruce A, Antonelli J, Young V, Mair J, Akram A, Hirani N, Koch O, Mackintosh C, Norrie J, Dear JW, Dhaliwal K. Evaluation of new or repurposed treatments for COVID-19: protocol for the phase Ib/IIa DEFINE trial platform. BMJ Open. 2021 Dec 15;11(12):e054442. doi: 10.1136/bmjopen-2021-054442.
citation: Quinn TM, Gaughan EE, Bruce A, Antonelli J, O'Connor R, Li F, McNamara S, Koch O, MacKintosh C, Dockrell D, Walsh T, Blyth KG, Church C, Schwarze J, Boz C, Valanciute A, Burgess M, Emanuel P, Mills B, Rinaldi G, Hardisty G, Mills R, Findlay EG, Jabbal S, Duncan A, Plant S, Marshall ADL, Young I, Russell K, Scholefield E, Nimmo AF, Nazarov IB, Churchill GC, McCullagh JSO, Ebrahimi KH, Ferrett C, Templeton K, Rannard S, Owen A, Moore A, Finlayson K, Shankar-Hari M, Norrie J, Parker RA, Akram AR, Anthony DC, Dear JW, Hirani N, Dhaliwal K. Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics. EBioMedicine. 2022 Feb;76:103856. doi: 10.1016/j.ebiom.2022.103856. Epub 2022 Feb 11.
citation: Gaughan EE, Quinn TM, Mills A, Bruce AM, Antonelli J, MacKinnon AC, Aslanis V, Li F, O'Connor R, Boz C, Mills R, Emanuel P, Burgess M, Rinaldi G, Valanciute A, Mills B, Scholefield E, Hardisty G, Findlay EG, Parker RA, Norrie J, Dear JW, Akram AR, Koch O, Templeton K, Dockrell DH, Walsh TS, Partridge S, Humphries D, Wang-Jairaj J, Slack RJ, Schambye H, Phung D, Gravelle L, Lindmark B, Shankar-Hari M, Hirani N, Sethi T, Dhaliwal K. An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE). Am J Respir Crit Care Med. 2023 Jan 15;207(2):138-149. doi: 10.1164/rccm.202203-0477OC.
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.