Antiretroviral Activity and Pharmacokinetics of Deferiprone in Healthy Volunteers and Asymptomatic HIV-infected Subjects

A Double Blind, Placebo-controlled, Dose-escalating, Multiple Dose Study, Investigating the Safety, Antiretroviral Activity, Tolerability and Pharmacokinetic Profile of Deferiprone When Administered in Healthy Volunteers and Asymptomatic HIV Infected Subjects

The purpose of this study was to examine the safety, efficacy, and pharmacokinetics of different dosages of deferiprone in subjects with or without HIV infection.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Deferiprone

Detailed Description

Three cohorts were enrolled: two of individuals who were asymptomatically infected with HIV and one of healthy volunteers. Dosages were as follows:

• Cohort 1 (asymptomatic HIV infected subjects): 33 mg/kg deferiprone three times daily for a total of 99 mg/kg/day
• Cohort 2 (healthy volunteers): 50 mg/kg deferiprone three times daily for a total of 150 mg/kg/day
• Cohort 3 (asymptomatic HIV infected subjects): 50 mg/kg deferiprone three times daily for a total of 150 mg/kg/day

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Bloemfontein,, South Africa, 9324
    • PAREXEL International

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged ≥18 years and ≤ 60 years.
• Absolute neutrophil count (ANC) of >1000/mm3 for African black population and ≥ 1600/mm3 for all other races.
• For Cohort 2: HIV-negative
• For Cohorts 1 and 3: HIV-1 positive; CD4 count of at least 300/mm3; HIV-1 RNA copies (viral load) >10 000 copies/mL serum; and current physical health stable and not requiring antiretroviral treatment
• For Cohorts 1 and 3: Chest x-ray showing absence of active infectious diseases (such as tuberculosis, viral or atypical bacteria or parasitic infection).

Exclusion Criteria:

• Presence of any severe concomitant disease.
• History of or current, recurrent or recent (4 weeks) febrile disease.
• History of opportunistic infections, neoplasm or AIDS-defining conditions.
• Inability to discontinue any medication from screening onwards, or for at least 2 weeks before the first admission; in particular any antiviral or therapy with immunosuppressive activity.
• Significant liver impairment: aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≥ 2.5 times the upper normal limit.
• Significant kidney impairment: serum creatinine ≥ two times the upper normal limit.
• Any concomitant disorder or resultant therapy likely to have interfered with subject compliance or with study procedures.
• Known hypersensitivity to any of the test materials or related compounds.
• Positive test for Hepatitis B and/or C antibodies.
• A history of multiple and/or severe allergies to drugs or foods or a history of anaphylactic reactions.
• History of seizures or epilepsy.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Subjects in this arm were asymptomatic HIV-infected individuals who received a dose of 33 mg/kg deferiprone three times a day for a total daily dosage of 99 mg/kg	Drug: Deferiprone; Oral iron chelator; Other Names: Ferriprox; L1
Experimental: Cohort 2; Subjects in this arm were healthy volunteers who received a dose of 50 mg/kg deferiprone three times a day for a total daily dosage of 150 mg/kg	Drug: Deferiprone; Oral iron chelator; Other Names: Ferriprox; L1
Experimental: Cohort 3; Subjects in this arm were asymptomatic HIV-infected individuals who received a dose of 50 mg/kg deferiprone three times a day for a total daily dosage of 150 mg/kg.	Drug: Deferiprone; Oral iron chelator; Other Names: Ferriprox; L1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of adverse events following repeated oral doses of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	Collection of adverse events, including abnormal findings in physical examination, vital signs, 12-lead ECG, 24-hour Holter ECG, and laboratory variables (hematology, clinical chemistry, and urinalysis)	9 weeks (from receipt of first dose until 8 weeks after the last dose)
Measurement of viral load following repeated oral doses of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	Measurement of HIV RNA load for the assessment of antiretroviral activity	9 weeks (pre-dose until 8 weeks after last dose)
Cluster of differentiation 4 (CD4) count and p24 antigen status following repeated oral doses of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	Measurement of CD4 count and p24 antigen status for assessment of antiviral activity	1 week (pre-dose to day of last dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of deferiprone and deferiprone 3-O-glucuronide	Determination of Cmax following a dose of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	24-hour interval
Tmax of deferiprone and deferiprone 3-O-glucuronide	Determination of Tmax of deferiprone and its metabolite following a dose of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	24-hour interval
Area under the curve (AUC) 0-infinity of deferiprone and deferiprone 3-O-glucuronide	Determination of AUC 0-infinity of deferiprone and its metabolite following a dose of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	24-hour interval
T1/2 of deferiprone and deferiprone 3-O-glucuronide	Determination of T1/2 of deferiprone and its metabolite following a dose of deferiprone in asymptomatic HIV-infected subjects and healthy volunteers	24-hour interval

Collaborators and Investigators

• Sponsor: ApoPharma
• Investigators: Principal Investigator: Dewald Steyn, MD, University of the Free State, South Africa

Publications and helpful links

General Publications

• Saxena D, Spino M, Tricta F, Connelly J, Cracchiolo BM, Hanauske AR, D'Alliessi Gandolfi D, Mathews MB, Karn J, Holland B, Park MH, Pe'ery T, Palumbo PE, Hanauske-Abel HM. Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial. PLoS One. 2016 May 18;11(5):e0154842. doi: 10.1371/journal.pone.0154842. eCollection 2016.

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: July 14, 2014
• First Submitted That Met QC Criteria: July 14, 2014
• First Posted (Estimate): July 16, 2014

Study Record Updates

• Last Update Posted (Estimate): July 16, 2014
• Last Update Submitted That Met QC Criteria: July 14, 2014
• Last Verified: November 1, 2007

More Information

Terms related to this study

• Keywords: HIV; iron chelation; deferiprone
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferiprone
• Other Study ID Numbers: LA26-106