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

Primary Purpose

COVID-19 Respiratory Infection

Status

Unknown status

Phase

Phase 1

Locations

India

Study Type

Interventional

Intervention

Topotecan

About this trial

This is an interventional treatment trial for COVID-19 Respiratory Infection focused on measuring Topotecan, hypoxia

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Christian Medical CollegeRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Topotecan

Arm Description

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: IV Dexamethasone 6mg once daily for at least 5 days and not more than 10 days. IV Remdesivir 200mg loading dose on day 1 followed by 100mg once daily for 4 days.

Outcomes

Primary Outcome Measures

Maximal tolerable dose of Topotecan

To determine a maximal dose of Topotecan, at which less than 1 out of 3 patients exhibit anti-cancer concentrations in plasma, or have G2/3/4 neutropenia

Secondary Outcome Measures

Rate of reduction in the duration of supplemental oxygen requirement in participants

Determine effect of Topotecan on duration of additional oxygen requirements

Rate of treatment related CTCAE grade 3/4 haematological toxicity

Dose limiting toxicities will be graded using CTCAE version 5.0.

Number of participant with Serious Adverse Events

Serious Adverse Events experience by subject after Topotecan administration (related and unrelated).

Proportion of patients requiring ICU care

Number of patients requiring intubation/inotropic/vasopressor support

Proportion of patients requiring mechanical ventilation

Number of patients requiring mechanical ventilation

Time to discharge

Time to hospital discharge in days

Proportion of patients with secondary infections

Number of patients with secondary infections

Proportion of patients who died after enrolment into trial

Death from related and unrelated causes

Full Information

NCT ID

NCT05083000

First Posted

October 11, 2021

Last Updated

October 27, 2021

Sponsor

National University Hospital, Singapore

Collaborators

Christian Medical College, Vellore, India

1. Study Identification

Unique Protocol Identification Number

NCT05083000

Brief Title

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

Official Title

Phase I Dose-escalation Study of Topotecan in Moderate-severe COVID-19 Patients

Study Type

Interventional

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Unknown status

Study Start Date

August 16, 2021 (Actual)

Primary Completion Date

December 31, 2021 (Anticipated)

Study Completion Date

March 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National University Hospital, Singapore

Collaborators

Christian Medical College, Vellore, India

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19 Respiratory Infection

Keywords

Topotecan, hypoxia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

The dose escalation will be in a standard 3+3 dose escalation design with 0.25mg increments of Topotecan; it will begin with a single dose 0.25mg for 3 patients-expanded to another 3 if no toxicities are seen. Subsequent dose levels will be 2 doses of 0.25mg, a single dose of 0.5mg and then 2 doses of 0.5mg (maximum of 24 patients).

Masking

None (Open Label)

Allocation

N/A

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Topotecan

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Topotecan

Other Intervention Name(s)

Topotecan hydrochloride

Intervention Description

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.

Primary Outcome Measure Information:

Title

Maximal tolerable dose of Topotecan

Description

To determine a maximal dose of Topotecan, at which less than 1 out of 3 patients exhibit anti-cancer concentrations in plasma, or have G2/3/4 neutropenia

Time Frame

24 hours and 14 days from the time of Topotecan administration

Secondary Outcome Measure Information:

Title

Rate of reduction in the duration of supplemental oxygen requirement in participants

Description

Determine effect of Topotecan on duration of additional oxygen requirements

Time Frame

1 week from administration of Topotecan

Title

Rate of treatment related CTCAE grade 3/4 haematological toxicity

Description

Dose limiting toxicities will be graded using CTCAE version 5.0.

Time Frame

Up to Day 10 from Topotecan administration

Title

Number of participant with Serious Adverse Events

Description

Serious Adverse Events experience by subject after Topotecan administration (related and unrelated).

Time Frame

Within 14 days from Topotecan administration

Title

Proportion of patients requiring ICU care

Description

Number of patients requiring intubation/inotropic/vasopressor support

Time Frame