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Atazanavir/Ritonavir and Zinc Pharmacokinetic Study (SSAT043)

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ClinicalTrials.gov Identifier: NCT01475227
Recruitment Status : Completed
First Posted : November 21, 2011
Last Update Posted : March 22, 2012
Sponsor:
Information provided by (Responsible Party):
St Stephens Aids Trust

Study Description
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Brief Summary:

The study is being conducted as the most common side effect of the HIV drug atazanavir (taken with ritonavir) is hyperbilirubinaemia. Bilirubin is a normal waste product from the body and gets broken down in the liver so it can leave the body through the gut. Atazanavir slows the breakdown of this chemical, which can cause jaundice (yellowing of the skin) and/or scleral icterus (yellowing of the eyes). This is completely harmless; in fact up to 1 in 10 of the UK population have an inherited condition that causes the same yellowing. However, some patients don't like this side effect and it is the commonest reason for switching off the drug.

A study in people with Gilberts syndrome (the inherited condition that causes the same changes in the chemical bilirubin) showed that a mineral supplement (zinc sulphate) reduced the levels of bilirubin in the blood. The aim of this study is to see if using zinc supplements can achieve the same effect in patients with high bilirubin due to atazanavir use.


Condition or disease Intervention/treatment Phase
HIV Infection Drug: 1 Solvazinc tablet, day 2 to day 15 Drug: 1 Solvazinc tablet, day 15 to day 28 Phase 4

Detailed Description:

Atazanavir is a protease inhibitor (PI) and, like other agents in this class, requires pharmacological 'boosting' with the cytochrome p450 inhibitor ritonavir. Ritonavir slows the hepatic clearance of PIs, increasing plasma concentration and allowing the us eof lower, and less frequent doses. Atazanavir, boosted with ritonavir, is approved for once-daily use, is an internationally preferred first-line agent (in combination with a backbone of two nucleosides [NRTI]) and the most commonly prescribed PI in the UK. Once-daily atazanavir/ritonavir with two NRTI is an effective and well-tolerated therapeutic option for people living with HIV infection. The most common adverse event associated with atazanavir use is unconjugated hyperbilirubinaemia. This is observed in over 40% of patients and up to 5% of patients discontinue the drug due jaundice and/or scleral icterus.

Truvada is a fixed dose combination of two NRTI, tenofovir (245mg) and emtricitabine (200mg), administered as one tablet once daily. Truvada is a preferred NRTI backbone in national and international guidelines and the first line, therefore most commonly used, NRTI backbone in our unit.

Benefits of atazanavir/ritonavir compared with alternative agents include once daily dosing, low pill burden, low rates of gastro-intestinal toxicity and, importantly in a patient population already at an elevated risk of cardiovascular disease, a favourable lipid profile. If a simple intervention could reduce the incidence of hyperbilirubinaemia this could reduce the risk of treatment discontinuation/switch. The aim of this study is to explore the benefit, and safety, of adding zinc sulphate in patients on a stable regimen of Truvada, atazanavir and ritonavir.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Crossover Study of the Effects of Zinc Sulphate Supplementation on Atazanavir/Ritonavir-associated Hyperbilirubinemia
Study Start Date : December 2011
Actual Primary Completion Date : March 2012
Actual Study Completion Date : March 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Jaundice
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A- early Solvazinc group
Zinc sulphate 125mg (1 Solvazinc tablet) once daily orally after dissolution in water, day 2 to day 15
 Drug: 1 Solvazinc tablet, day 2 to day 15
Zinc sulphate 125mg, day 2 to day 15
Other Name: Zinc sulphate
Experimental: Arm B- late Solvazinc group
Zinc sulphate 125mg (1 Solvazinc tablet) once daily orally after dissolution in water, day 15 to day 28
 Drug: 1 Solvazinc tablet, day 15 to day 28
Zinc sulphate 125mg, day 15 to day 28
Other Name: Zinc sulphate


Outcome Measures
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Primary Outcome Measures :
  1. To assess the change in unconjugated hyperbilirubinaemia following acute and chronic administration of zinc sulphate during atazanavir/ritonavir therapy. [ Time Frame: baseline and day 29 ]
    Change in serum unconjugated bilirubin concentrations when atazanavir/ritonavir is added to zinc sulphate, adjusted for period effect


Secondary Outcome Measures :
  1. safety and tolerability of zinc sulphate supplement when given concomitantly with atazanavir/ritonavir [ Time Frame: baseline and day 14 ]
    Assessment of the impact of adding zinc sulphate to atazanavir/ritonavir-based HAART on grade 2-4 laboratory abnormalities and adverse events.

  2. To assess atazanavir plasma exposure in the presence of zinc and relationship between the latter and hyperbilirubin during zinc intake. [ Time Frame: baseline and day 14 ]
    Atazanavir plasma exposure in the presence of zinc and relationship between the latter and hyperbilirubin during zinc intake.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The ability to understand and sign a written informed consent form, prior to participation in any screening procedure and must be willing to comply with all study requirements
  2. Male or non-pregnant, non-lactating females.
  3. Aged between 18 to 65 years, inclusive.
  4. Documented HIV-1 infection
  5. Plasma HIV RNA less than 40 copies/mL (note retesting of screening viral load is allowed).
  6. CD4 count > 100 at screening (note retesting of screening CD4 count is allowed).
  7. Receiving an antiretroviral regimen of Truvada and atazanavir/ritonavir for more than 3 months.
  8. Serum total bilirubin concentration greater than 25 micromol/L
  9. Agrees not to change regimen, outside the study recommendations, from baseline until end of the treatment period unless this is medically indicated as decided by their treating physician.

Exclusion Criteria:

  1. Any serious or active medical or psychiatric illness, which, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include any active clinically significant renal, cardiac, hepatic, pulmonary, vascular, metabolic disorders or malignancy.
  2. Body mass index (BMI) >35 kg/m2

  3. Presence of any current active AIDS defining illness (Category C conditions according to the CDC Classification System for HIV Infection 1993) with the following exceptions:

    • Stable cutaneous Kaposi's Sarcoma

  4. Clinically relevant alcohol or drug use (positive urine drug screen, with the exception of cannabinoids) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events.
  5. The use of zinc supplements for 1 month before screening and disallowed concomitant therapy (See Concomitant Medication and treatment, section 5.2) or medication that may interfere with the study results (as determined by the principal investigator).
  6. Females of childbearing potential who are not using effective non-hormonal birth control methods or not willing to continue using these birth control methods for at least 14 days after the end of the treatment period.
  7. Previous allergy to any of the constituents of the zinc sulphate tablets administered in this trial.
  8. Subjects with laboratory evidence of significantly decreased hepatic or renal function (as determined by the principal investigator).
  9. Exposure to any investigational drug or placebo within 4 weeks of first dose of study drug
Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01475227


Locations
United Kingdom
St Stephen's AIDS Trust
London, United Kingdom, SW10 9NH
Sponsors and Collaborators
St Stephens Aids Trust
Investigators
Principal Investigator: Marta Boffito, Dr St Stephen's AIDS Trust
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party: St Stephens Aids Trust
ClinicalTrials.gov Identifier: NCT01475227     History of Changes
Other Study ID Numbers: SSAT 043
First Posted: November 21, 2011    Key Record Dates
Last Update Posted: March 22, 2012
Last Verified: March 2012

Keywords provided by St Stephens Aids Trust:
HIV
Bilirubin

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Atazanavir Sulfate
Zinc
Zinc Sulfate
HIV Protease Inhibitors
Protease Inhibitors
 Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Astringents
Dermatologic Agents