A5336A Phase IIa, Double-blind, Placebo-controlled,

Randomized Trial of Ruxolitinib in Antiretroviral-treated HIV-Infected Adults

CAB Draft DiscussionTuesday, January 14, 2014

CWRU/UH CRS CAB Meeting

Inflammation

Anti-HIV medicines have been very successful in allowing people with HIV to control the virus.

However, researchers have noticed that many patients have high levels of inflammation even when their medicine is controlling their HIV viral load.

Inflammation is the body’s response to infection or irritation that can be helpful sometimes but can cause long-term problems when it lasts too long.

Researchers believe that people with high levels of inflammation could, over time, have an increased risk to develop certain health problems such as heart disease and some forms of cancer.

Cytokines

Examples: Some cytokines are chemical switches that turn certain immune cell types on and off. For example, one cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells.

One group of cytokines chemically attracts specific cell types. These so-called chemokines are released by cells at a site of injury or infection and call other immune cells to the region to help repair the damage or fight off the invader.

A cytokine is a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells.

SchemaDesign: Multi-center, phase IIa, randomized, double-blind, placebo-controlled trial.

Duration: 12 weeks. 9 visits including screening visit.

Sample size: 60 subjects on continuous ART medicine for at least 2 years, with no plans to change medicines for duration of study. Regimen must include either TDF/FTC or ABC/3TC plus an NNRTI or INSTI for at least two months. (At least 15 participants must be on ART medicine efavirenz (EFV) to evaluate effect of study drug on EFV).

Population: HIV infected adults (> 18 years old) on stable ART containing either an NNRT or integrase strand transfer inhibitor. Must have virologic suppression (at least 2 viral loads under 50; with no viral loads greater than 50 for 12 months prior to entry. Not more than one viral load between 50 and 200 for at least 2 years). CD4 call count 350 or higher.

Study drug: Randomized 3:1 Ruxolitinib 10 mg orally twice daily or placebo orally twice daily for five weeks.

Ruxolinitib

Ruxolitinib is an FDA-approved medicine for the treatment of myelofibrosis, a disorder in which bone marrow is replaced by scar (fibrosis) tissue. Myelofibrosis can lead to leukemia.

Many of the cytokines affected by myelofibrosis are also affected by HIV. Because ruxolitinib acts on these cytokines, it is proposed that is may also reduce inflammation in the bodies of people living with HIV.

Primary Objective

To evaluate the safety and tolerability of ruxolitinib in ART-treated HIV-1 virologically suppressed infected subjects and compare changes in IL-6 levels between subjects randomized to ruxolitinib and those randomized to placebo, during 5 weeks of treatment.