Reducing Hypoxia in Patients With Coronavirus Disease (COVID-19) Using Topotecan With Standard of Care

NCT ID: NCT05083000

Last Updated: 2021-11-04

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-16
• Study Completion Date: 2022-03-31

Brief Summary

The primary objective of the phase 1 trial is to identify a dose of topotecan that will be safe to take forward into a Phase 2 trial, with no unexpected toxicities or drug-drug interactions with standard therapy for COVID-19. The investigators hypothesise that a single dose of low-dose Topotecan will blunt the expression of inflammatory genes in patients with moderate COVID-19, without cytotoxic side effects.

Detailed Description

4 fixed dosing levels (0.25 -0.5mg) of Topotecan will be evaluated in this trial, using sub-cytotoxic doses of Topotecan which are well below typical chemotherapy levels and shown not to cause myelosuppression in previously tested populations. The dose escalation will be in a standard 3+3 dose escalation design with 0.25 mg increments of Topotecan. The study aims to establish the recommended phase 2 dose (RP2D) of Topotecan in hypoxic patients with moderate to severe COVID-19.The RP2D is defined as the maximum safe dose at which 3 or more patients are found to have clinically relevant concentrations of Topotecan in the blood stream, without reaching anti-cancer concentrations in plasma (defined as Area under the curve (AUC)>150000) and without causing Grade 2/3/4 neutropenia (CTCAE5).

Conditions

COVID-19 Respiratory Infection

Keywords

Topotecan; hypoxia

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Topotecan

Subject will receive Topotecan as a single dose or 2 consecutive doses given via intravenous (IV). The starting dose level of Topotecan is 0.25mg. Subsequent dose levels will be 2 doses of 0.25mg, a single dose of 0.5mg and then 2 doses of 0.5mg.

Standard of care treatments for COVID-19 will be given together if available as per the following protocol:

1. IV Dexamethasone 6mg once daily for at least 5 days and not more than 10 days.

2. IV Remdesivir 200mg loading dose on day 1 followed by 100mg once daily for 4 days.

Group Type: EXPERIMENTAL

Topotecan

Intervention Type: DRUG

Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitor activity. It is a well-established chemotherapeutic agent used for cancer treatment.

Interventions

Topotecan

Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitor activity. It is a well-established chemotherapeutic agent used for cancer treatment.

Intervention Type: DRUG

Other Intervention Names

Topotecan hydrochloride

Eligibility Criteria

Inclusion Criteria

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by at least 1 positive Polymerase Chain Reaction (PCR) test
• Moderate COVID as evidenced by Oxygen saturation <93% on room air (or <88% if prior CLD)
• Admission to emergency department for monitoring and/or supportive care:
• The following biochemical markers:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. Platelets ≥ 100 x 109/L, Haemoglobin ≥ 9x 109/L.
• Bilirubin < 1.5 times upper limit of normal (ULN). Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 2.5 times ULN.
• Calculated creatinine clearance of ≥ 30ml/min calculated using the formula of Cockcroft and Gault: (140-age) x mass (kg)/)72x creatinine mg/dl); multiple by 0.85 if female.
• Laboratory features of cytokine release, as defined by any 1 of the following:

i. C-reactive protein (CRP)> 75mg/L ii. Lactate Dehydrogenase (LDH) > ULN iii. D-dimer > 1.0 mg/L iv. Ferritin > 500ng/ml v. Elevated Interleukin-6 levels

Exclusion Criteria

• Patients requiring mechanical ventilation
• Any immunosuppressive medication including chemotherapy(excluding steroids) administered concurrently or within last 14 days.
• Patients with uncontrolled diabetes mellitus (HbA1C within 1 month >8)
• Pregnancy or Breastfeeding.
• Known allergy to Topotecan. Unconjugated hyperbilirubinemia on a fasting Liver Function Test (LFT), which can indicate Gilberts Syndrome.
• Suspected active bacterial, fungal, or other infection in addition to COVID-19.
• Any condition that would, in the opinion of the Investigator, increase the risk of the participant
• by participating in the study.
• Inability to provide consent.
• Unable to comply with study procedures.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Christian Medical College, Vellore, India

OTHER

Sponsor Role: collaborator

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anand JEYASEKHARAN

Role: PRINCIPAL_INVESTIGATOR

National University Hospital, Singapore

Locations

Christian Medical College

Vellore, Tamil Nadu, India

Site Status: RECRUITING

Countries

India

Central Contacts

Anand JEYASEKHARAN

Role: CONTACT

Phone: +65 6779 5555

Email: anand_jeyasekharan@nuhs.edu.sg

Anand JEYASEKHARAN

Role: CONTACT

Facility Contacts

Ajoy Oommen John

Role: primary

Ashish Singh

Role: backup

Other Identifiers

TOTORO1

Identifier Type: -

Identifier Source: org_study_id