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Atazanavir/Ritonavir and Zinc Pharmacokinetic Study (SSAT043)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
St Stephens Aids Trust
ClinicalTrials.gov Identifier:
NCT01475227
First received: October 31, 2011
Last updated: March 21, 2012
Last verified: March 2012
History of Changes
  Purpose

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 Intervention Phase
HIV Infection
 Drug: 1 Solvazinc tablet, day 2 to day 15
Drug: 1 Solvazinc tablet, day 15 to day 28
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Crossover Study of the Effects of Zinc Sulphate Supplementation on Atazanavir/Ritonavir-associated Hyperbilirubinemia

Resource links provided by NLM:

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

Further study details as provided by St Stephens Aids Trust:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Change in serum unconjugated bilirubin concentrations when atazanavir/ritonavir is added to zinc sulphate, adjusted for period effect


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

  • 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 ] [ Designated as safety issue: No ]
    Atazanavir plasma exposure in the presence of zinc and relationship between the latter and hyperbilirubin during zinc intake.
Enrollment: 16
Study Start Date: December 2011
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility
Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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

No publications provided

Responsible Party: St Stephens Aids Trust
ClinicalTrials.gov Identifier: NCT01475227     History of Changes
Other Study ID Numbers: SSAT 043
Study First Received: October 31, 2011
Last Updated: March 21, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by St Stephens Aids Trust:
HIV
Bilirubin

Additional relevant MeSH terms:
Zinc
Zinc Sulfate
Astringents
Dermatologic Agents
Growth Substances
 Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on March 03, 2015