HIV InfectionPhase 1SSAT039NCT01232660
Hydroxychloroquine for Discordant CD4 Responders on Highly Active Antiretroviral Therapy (HAART)
A Phase 1 study testing Hydroxychloroquine in people with HIV Infection, run by St Stephens Aids Trust at 1 site in United Kingdom.
Trial summary
The purpose of the study is to examine the effects of adding a drug called hydroxychloroquine, usually used to treat rheumatoid arthritis, to patients' usual antiretroviral combination. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV Infection
- What is being tested?
- Hydroxychloroquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Oct 2010to Aug 2014
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented HIV infection
- Age 18 to 65 years.
- On stable antiretroviral therapy for at least 96 weeks
- CD4 count less than 350 on screening blood test and on one other test performed within 4 months prior to screening and less than 150 cell rise in CD4 count in last 3 years
- Expression of CD38 on CD8+ T cells >10%
- Plasma HIV RNA viral load less than 50 copies/ml on screening blood test and for at least 72 weeks prior to screening (blips defined as a single viral load >50 and <500 copies/ml preceded and followed by an undetectable result will be permitted)
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- Willing and able to provide written informed consent
- Females of child-bearing potential will need to use effective contraception
- Satisfactory ophthalmological assessment including:
- visual acuity
- careful ophthalmoscopy
- fundoscopy
- central visual field testing with a red target
- colour vision.
Who cannot join
- History of psoriasis, porphyria cutanea tarda, epilepsy, myasthenia gravis, myopathy, cardiac arrhythmias or glucose 6-phosphate dehydrogenase (G6PD) deficiency.
- Insulin-dependent or non-insulin-dependent diabetes mellitus.
- Chronic liver disease of any cause or alcoholism (investigator defined)
- Pneumonia, meningitis, septicaemia or any other serious infection in the 2 months prior to screening.
- Any acute infection with fever and systemic symptoms in the last 24 hours.
- Any vaccinations in the 2 months prior to screening.
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- Active malignancy (patients are eligible if treatment for the malignancy was completed more than 2 years prior to screening and there has been no subsequent clinical evidence of active disease or localised completely excised cutaneous cancers and low volume Kaposi's sarcoma) or any active immune-mediated or inflammatory disease.
- Any known suicide attempts (at any time in the past) or current or past history of depression requiring treatment within the 2 years prior to screening.
- A woman who is currently pregnant or breastfeeding.
- Use of systemic corticosteroids or other immunomodulatory drugs within the 12 months prior to screening.
- Current use of medication with known serious hepatotoxic effects or known interaction with hydroxychloroquine (section 5.2)
- Evidence of cardiac conduction defects or cardiac arrhythmia on screening ECG.
- Hepatitis B surface antigen (HBsAg) positive or Hepatitis C PCR positive (patients who are Hepatitis C antibody positive are allowed to enter if PCR is negative).
- Any of the following laboratory abnormalities on screening blood test:
- Haemoglobin less than 10.5g/dl
- Absolute neutrophil count less than 1.0x109/L
- Platelet count less than 100 X 109/L
- ALT or AST, or alkaline phosphatase above 2.5 x upper limit of normal (ULN) Template V 2.0, 06 April 2008 SSAT039 Page 23 of 73 Version 6.0, 17 October 2011
- Serum creatinine greater than 1.5xULN
- Estimated creatinine clearance (MDRD equation*) below 60ml/min
- Inability to attend or comply with treatment or follow-up scheduling.
- Current participation in any other clinical intervention trial.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site, 1 recruiting
- Recruiting
St Stephen's Centre
London, SW10 9NH
About this study
Official title: The Immunological Impact of Adding Hydroxychloroquine in Patients With Discordant CD4+ Cell Responses to Suppressive HAART: A Phase I Pilot Study.
The purpose of the study is to examine the effects of adding a drug called hydroxychloroquine, usually used to treat rheumatoid arthritis, to patients' usual antiretroviral combination. HIV causes activation of some parts of the immune system and this immune activation may persist despite effective antiretroviral therapy. Ongoing activation may be responsible for poor CD4 rise on antiretroviral therapy and for some HIV-related complications. Drugs like hydroxychloroquine work by inhibiting immune activation.
The study will primarily investigate the effect of adding this medication on immunological parameters (particularly CD4 count), on other safety parameters (such as cholesterol), patients' side effects and viral load.
If you decide to take part, the duration of your involvement in the study will be 24 weeks plus two screening visits up to 84 days prior to the start of the study and a follow up visit.
Read the detailed description
Studies exploring changes in antiretrovirals or addition of antiretrovirals from new classes in patients with discordant immune response to suppressive HAART have, in general, yielded disappointing results.
The addition of the antiretroviral maraviroc (a CCR5 antagonist) in patients who had been on suppressive HAART for at least a year but with a CD4 count less than 250 (and not rising) yielded no improvement in CD4 counts in 6 individuals after approximately 5 months.
A small study investigating the benefit of switching to lopinavir/ritonavir (predominantly from NNRTI-based therapy) showed a significant improvement in CD4 cell count with a reduction in cell apoptosis at 6 months.However, data for other switches are lacking and lopinavir/ritonavir may not be a preferred switch option due to gastrointestinal tolerability and an increased risk of myocardial infarction in cohort analyses.
Chronic HIV infection is characterised by gradual loss of CD4 T-cells by direct (virus mediated CD4 death) and indirect mechanisms. Increased immune activation is an indirect mechanism that is central to CD4 T-cell loss. In observational studies, the level of immune activation is associated with the rate of CD4 decline and in patients taking antiretroviral therapy (with or without complete viral suppression) the extent of CD4 recovery is associated with the degree of immune activation.
Immune activation has also been shown to correlate with disease progression and survival. The causes of generalized immune activation in HIV are not fully understood but may be related to nef or gp120.
Hydroxychloroquine [Plaquanil®] is licensed to treat rheumatoid arthritis and other inflammatory conditions; it is related to the antimalarial chloroquine.
Hydroxychloroquine and chloroquine have long been used as immunomodulatory therapies for T-cell mediated disorders. The exact mechanisms of hydroxychloroquine are not fully understood, but the agent appears to affect T-cell proliferation and signalling. Hydroxychloroquine also inhibits T-cell proliferative responses and production of pro-inflammatory cytokines IL-1 and IL-6.
Hydroxychloroquine and chloroquine have been shown to inhibit HIV replication, regardless of viral clade or co-receptor tropism, and promote CD4 immune protection.
Three small clinical trials of hydroxychloroquine have been reported in HIV-infected patients. Hydroxychloroquine was associated with small to modest reductions in viral load both as monotherapy and as part of combination therapy. In one of these studies, hydroxychloroquine was compared with zidovudine in HIV-infected patients and patients in both groups had reduced levels of plasma HIV-1 RNA and serum p24 antigen after 16 weeks. Interleukin-6 (an inflammatory cytokine associated with increased risk of mortality in cohort studies of HIV) levels were significantly reduced in the hydroxychloroquine group but not in the zidovudine group.
The usual minimum effective dose of hydroxychloroquine is 400mg once daily (administered as two 200mg film-coated tablets) administered orally. This is also the dose selected for an ongoing Medical Research Council study investigating the immune benefits of hydroxychloroquine in treatment-naive patients not needing to start antiretrovirals. Hydroxychloroquine is cumulative in action and requires several weeks to exert its beneficial effects; for rheumatic disease, treatment should be discontinued if there is no improvement by 6 months. On this basis we feel that 3 months is sufficient time to detect most improvement in immune activation and 6 months sufficient time to observe any benefits if they occur. The maximum recommended dose of hydroxychloroquine is 6.5mg/kg/day.
- Conditions
- HIV Infection
- Being tested
- Hydroxychloroquine
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hydroxychloroquine 400mg once daily orally
| Study group | Role | What they receive |
|---|---|---|
| Delayed | Active comparator | Delayed addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART Receives: Drug: Hydroxychloroquine |
| Immediate | Experimental | Immediate addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART Receives: Drug: Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in CD4 from baseline
To measure the change in CD4 from baseline after 12 weeks of hydroxychloroquine therapy
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Nov 2010 (estimated)
- Study startOct 2010
- Primary completionAug 2014 (estimated)
- Study completionAug 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- St Stephens Aids Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Laura Waters, Dr, Principal investigator, St Stephen's AIDS Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01232660
- Sponsor's protocol ID
- SSAT 039
- Acronym
- SSAT039
- Status last verified
- Feb 2014
- First submitted
- 29 Oct 2010
- Last updated
- 11 Feb 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Immunological Impact of Adding Hydroxychloroquine in Patients With Discordant CD4+ Cell Responses to Suppressive HAART: A Phase I Pilot Study.
- ClinicalTrials.gov ID
- NCT01232660
- Acronym / sponsor ID
- SSAT039 / SSAT 039
- Conditions
- HIV Infection
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- St Stephens Aids TrustUniversity, hospital or other
- Study start
- Oct 2010
- Primary completion
- Aug 2014 (estimated)
- Study completion
- Aug 2014 (estimated)
- First posted
- 2 Nov 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to examine the effects of adding a drug called hydroxychloroquine, usually used to treat rheumatoid arthritis, to patients' usual antiretroviral combination. HIV causes activation of some parts of the immune system and this immune activation may persist despite effective antiretroviral therapy. Ongoing activation may be responsible for poor CD4 rise on antiretroviral therapy and for some HIV-related complications. Drugs like hydroxychloroquine work by inhibiting immune activation.
The study will primarily investigate the effect of adding this medication on immunological parameters (particularly CD4 count), on other safety parameters (such as cholesterol), patients' side effects and viral load.
If you decide to take part, the duration of your involvement in the study will be 24 weeks plus two screening visits up to 84 days prior to the start of the study and a follow up visit.
Detailed description
Studies exploring changes in antiretrovirals or addition of antiretrovirals from new classes in patients with discordant immune response to suppressive HAART have, in general, yielded disappointing results.
The addition of the antiretroviral maraviroc (a CCR5 antagonist) in patients who had been on suppressive HAART for at least a year but with a CD4 count less than 250 (and not rising) yielded no improvement in CD4 counts in 6 individuals after approximately 5 months.
A small study investigating the benefit of switching to lopinavir/ritonavir (predominantly from NNRTI-based therapy) showed a significant improvement in CD4 cell count with a reduction in cell apoptosis at 6 months.However, data for other switches are lacking and lopinavir/ritonavir may not be a preferred switch option due to gastrointestinal tolerability and an increased risk of myocardial infarction in cohort analyses.
Chronic HIV infection is characterised by gradual loss of CD4 T-cells by direct (virus mediated CD4 death) and indirect mechanisms. Increased immune activation is an indirect mechanism that is central to CD4 T-cell loss. In observational studies, the level of immune activation is associated with the rate of CD4 decline and in patients taking antiretroviral therapy (with or without complete viral suppression) the extent of CD4 recovery is associated with the degree of immune activation.
Immune activation has also been shown to correlate with disease progression and survival. The causes of generalized immune activation in HIV are not fully understood but may be related to nef or gp120.
Hydroxychloroquine [Plaquanil®] is licensed to treat rheumatoid arthritis and other inflammatory conditions; it is related to the antimalarial chloroquine.
Hydroxychloroquine and chloroquine have long been used as immunomodulatory therapies for T-cell mediated disorders. The exact mechanisms of hydroxychloroquine are not fully understood, but the agent appears to affect T-cell proliferation and signalling. Hydroxychloroquine also inhibits T-cell proliferative responses and production of pro-inflammatory cytokines IL-1 and IL-6.
Hydroxychloroquine and chloroquine have been shown to inhibit HIV replication, regardless of viral clade or co-receptor tropism, and promote CD4 immune protection.
Three small clinical trials of hydroxychloroquine have been reported in HIV-infected patients. Hydroxychloroquine was associated with small to modest reductions in viral load both as monotherapy and as part of combination therapy. In one of these studies, hydroxychloroquine was compared with zidovudine in HIV-infected patients and patients in both groups had reduced levels of plasma HIV-1 RNA and serum p24 antigen after 16 weeks. Interleukin-6 (an inflammatory cytokine associated with increased risk of mortality in cohort studies of HIV) levels were significantly reduced in the hydroxychloroquine group but not in the zidovudine group.
The usual minimum effective dose of hydroxychloroquine is 400mg once daily (administered as two 200mg film-coated tablets) administered orally. This is also the dose selected for an ongoing Medical Research Council study investigating the immune benefits of hydroxychloroquine in treatment-naive patients not needing to start antiretrovirals. Hydroxychloroquine is cumulative in action and requires several weeks to exert its beneficial effects; for rheumatic disease, treatment should be discontinued if there is no improvement by 6 months. On this basis we feel that 3 months is sufficient time to detect most improvement in immune activation and 6 months sufficient time to observe any benefits if they occur. The maximum recommended dose of hydroxychloroquine is 6.5mg/kg/day.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Delayed | Active comparator | Drug: HydroxychloroquineDelayed addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART |
| Immediate | Experimental | Drug: HydroxychloroquineImmediate addition of hydroxychloroquine in patients with discordant CD4+ cell responses to suppressive HAART |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Documented HIV infection
- Age 18 to 65 years.
- On stable antiretroviral therapy for at least 96 weeks
- CD4 count less than 350 on screening blood test and on one other test performed within 4 months prior to screening and less than 150 cell rise in CD4 count in last 3 years
- Expression of CD38 on CD8+ T cells >10%
Key exclusion criteria (22 listed)
- History of psoriasis, porphyria cutanea tarda, epilepsy, myasthenia gravis, myopathy, cardiac arrhythmias or glucose 6-phosphate dehydrogenase (G6PD) deficiency.
- Insulin-dependent or non-insulin-dependent diabetes mellitus.
- Chronic liver disease of any cause or alcoholism (investigator defined)
- Pneumonia, meningitis, septicaemia or any other serious infection in the 2 months prior to screening.
- Any acute infection with fever and systemic symptoms in the last 24 hours.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydroxychloroquineHydroxychloroquine 400mg once daily orally | Drug | Delayed, Immediate |
Primary outcome
Change in CD4 from baseline
Time frame: 12 weeks
To measure the change in CD4 from baseline after 12 weeks of hydroxychloroquine therapy
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Feb 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Laura Waters, Dr principal investigator
St Stephen's AIDS Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Hydroxychloroquine in people with HIV Infection, run by St Stephens Aids Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Chris Higgs (0208 846 6135, chris.higgs@chelwest.nhs.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in CD4 from baseline (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2014.