VoriTDM: A Trial Comparing Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01416025
• Collaborator: Pfizer (Industry)
• Enrollment: 29
• Location: 1
• Arms: 2
• Duration (Months): 35
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This is a prospective, multicenter, randomized trial to study therapeutic drug monitoring (TDM) of voriconazole among patients with an invasive mould infection (IMI). The primary objective of this study will be to assess the effect of prospective voriconazole TDM on the composite of adverse events (AE) and clinical response.

Condition or Disease	Intervention/Treatment	Phase
Fungal Infection	Drug: Prospective TDM Arm	Phase 4

Detailed Description

This is a prospective study of patients who receive voriconazole as treatment for an IMI (proven, probable, and possible by the EORTC/MSG definitions), other than zygomycosis. Patients will be randomized to receive either standard dosing or dosing based on TDM, stratified by whether initial voriconazole therapy is PO or IV. Assessment of outcomes will be made 42 days after start of voriconazole. An additional follow up for safety reporting will be performed 4weeks after completion of voriconazole

The patients will be randomized to:

• Prospective TDM: voriconazole dose will be adjusted based on per protocol obtained TDM levels, and

• Standard dosing: standard doses of voriconazole will be used.

In the prospective TDM arm, voriconazole TDM will be performed in real time at each site and results will be reported to treating physicians for dose adjustment. All efforts will be taken to obtain results within 24 hours of blood sample collection. In the standard dosing arm, blood samples will be collected, stored, and batched for voriconazole levels to be tested retrospectively. Voriconazole plasma levels will be measured by validated high performance liquid chromatography (HPLC) assays as detailed. Voriconazole trough levels will be performed on Day Baseline/Screening, 5, 14, 28, and 42.

Voriconazole peak level will be measured on Day 5. Trough voriconazole levels will be obtained in case of an event, defined as suspected drug-associated toxicity and/or clinical failure.

Assessment of AEs for all patients will be monitored during the study and response to treatment will be assessed. The composite of overall AE/clinical failure will be assessed on day 42.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized Trial Comparing the Efficacy and Safety of Voriconazole Administered With Therapeutic Drug Monitoring vs. Standard Dosing
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prospective TDM Arm Voriconazole dose will be adjusted based on per protocol obtained TDM levels	Drug: Prospective TDM Arm; Voriconazole dose will be adjusted based on per protocol obtained TDM levels; Other Names: VFEND
No Intervention: Standard dosing Standard doses of voriconazole will be used

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Failure [42 days]

   The primary endpoint of the study will be a binary outcome, called Failure, defined as one of the following: measured at 42 days from initiation of drug administration: Progression of underlying infection (clinical failure) Death Development of a voriconazole-associated SAE: LFTs, Rash, Visual disturbance, Neurologic abnormality (e.g: hallucinations)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Indication for voriconazole administration: proven, probable, or possible IMI, excluding zygomycosis (based on the revised EORTC/MSG consensus definitions) [De Pauw, Clin Infect Dis. 2008; 46:1813].

• Male or female ≥12 years of age.

• Evidence of a personally signed and dated informed consent document in accordance with local regulatory and legal requirements indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.

• Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

• Known history of allergy, hypersensitivity or serious reaction to azole antifungals.

• Patients with aspergilloma or allergic bronchopulmonary aspergillosis (ABPA).

• Patients with chronic invasive aspergillosis with duration of symptoms or radiological finding for more than 4 weeks prior to study entry.

• Patients who are receiving and cannot discontinue the following drugs at least 24 hours prior to randomization: terfenadine, pimozide or quinidine (because of the possibility of QT prolongation), St John's wort preparation.

• Patients receiving any of the following medications: sirolimus, rifampin, rifabutin, carbamazepine, long acting barbiturates (e.g., phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).

• Receipt of more than 5 days of voriconazole as treatment prior to enrollment.

• Receipt of 7 days or more of systemic antifungal treatment for the current episode of IMI.

• Severe liver dysfunction (defined as total bilirubin, AST, ALT, or alkaline phosphatase >5x upper limit of normal). Local laboratory results may be used to qualify individuals for enrollment.

• Patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response, or make it unlikely that the proposed course of therapy can be completed.

• Patients who have already participated in this trial within the last 30 days.

• Patients with a high likelihood of death due to factors unrelated to IA (e.g., due to relapsed malignancy, severe GVHD, other underlying diseases, etc.) within 30 days following planned enrollment (investigator's discretion).

• Patients that weigh <45 and >120 kg, respectively, upon enrollment. If patients' weight is beyond those limits upon serial assessments during the study period, the study monitor should be contacted and decisions to keep or withdraw subject from the study will be made.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins	Baltimore	Maryland	United States	21205

Sponsors and Collaborators

• Johns Hopkins University
• Pfizer

Investigators

• Principal Investigator: Kieren Marr, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kieren Marr, Professor of Medicine and Oncology, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01416025
• Other Study ID Numbers: NA_00041916
• First Posted: Aug 12, 2011
• Last Update Posted: Aug 18, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Kieren Marr, Professor of Medicine and Oncology, Johns Hopkins University: Voriconazole; Therapeutic drug monitoring; Hematopoietic stem cell transplant; Hematologic malignancy; Invasive mould infection
• Additional relevant MeSH terms: Mycoses

Study Results

Participant Flow

Arm/Group Title	Prospective TDM Arm	Standard Dosing
Arm/Group Description	Voriconazole dose will be adjusted based on per protocol obtained TDM levels Prospective TDM Arm: Voriconazole dose will be adjusted based on per protocol obtained TDM levels	Standard doses of voriconazole will be used
Period Title: Overall Study
STARTED	14	15
COMPLETED	14	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Prospective TDM Arm	Standard Dosing	Total
Arm/Group Description	Voriconazole dose will be adjusted based on per protocol obtained TDM levels Prospective TDM Arm: Voriconazole dose will be adjusted based on per protocol obtained TDM levels	Standard doses of voriconazole will be used	Total of all reporting groups
Overall Participants	14	15	29
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 71.4%	10 66.7%	20 69%
>=65 years	4 28.6%	5 33.3%	9 31%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63.4	59.1	62.5
Sex: Female, Male (Count of Participants)
Female	5 35.7%	5 33.3%	10 34.5%
Male	9 64.3%	10 66.7%	19 65.5%
Region of Enrollment (participants) [Number]
United States	14 100%	15 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Failure
Description	The primary endpoint of the study will be a binary outcome, called Failure, defined as one of the following: measured at 42 days from initiation of drug administration: Progression of underlying infection (clinical failure) Death Development of a voriconazole-associated SAE: LFTs, Rash, Visual disturbance, Neurologic abnormality (e.g: hallucinations)
Time Frame	42 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prospective TDM Arm	Standard Dosing
Arm/Group Description	Voriconazole dose will be adjusted based on per protocol obtained TDM levels Prospective TDM Arm: Voriconazole dose will be adjusted based on per protocol obtained TDM levels	Standard doses of voriconazole will be used
Measure Participants	14	15
Number [participants]	1 7.1%	5 33.3%

Adverse Events

Arm/Group Title	Prospective TDM Arm		Standard Dosing
Arm/Group Description	Voriconazole dose will be adjusted based on per protocol obtained TDM levels Prospective TDM Arm: Voriconazole dose will be adjusted based on per protocol obtained TDM levels		Standard doses of voriconazole will be used
All Cause Mortality
	Prospective TDM Arm		Standard Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Prospective TDM Arm		Standard Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
hospitalization	0/14 (0%)	0	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Prospective TDM Arm		Standard Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/14 (21.4%)		4/15 (26.7%)
Psychiatric disorders
Stop voriconazole	3/14 (21.4%)	3	4/15 (26.7%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.