Hydroxychloroquine and Indapamide in SPMS

Description

In patients with SPMS, there is ongoing slow and continuous loss of nerve cells, which causes damage to the brain and spinal cord. This ultimately becomes noticeable as slowly and continuously worsening disability. While the cause of this ongoing damage is unknown, it appears that at least part of the damage may be caused by cells in the brain called "microglia" (a type of immune cell that resides in the brain and spinal cord). These microglial cells can have beneficial roles, for instance when they clear away debris, but they can also cause damage to brain cells. In SPMS, microglial cells are often found to be in a state of activation, and it is currently believed that this constant activation of microglial cells is likely an important cause of the ongoing damage to brain cells. Another harmful process affecting patients with SPMS is "oxidative stress". Oxidative stress occurs when immune cells in the brain and spinal cord are activated and produce substances that may damage nerve cells. Current treatments for MS mostly are meant to prevent relapses and are beneficial in relapsing-remitting MS, but so far there are no treatments that benefit people with SPMS who do not experience relapses. Better therapies are needed for SPMS, and it is believed that treatments that reduce the activation of microglial cells and oxidative stress may be useful.

The medication Hydroxychloroquine (HCQ) reduces the activity of human microglia in laboratory experiments. Animal experiments also showed that treatment with HCQ reduces disease severity in an animal model of MS. HCQ, therefore, may also reduce the activity of microglia in people with SPMS, and hopefully prevent or slow down the progression of disability in SPMS. HCQ is currently approved in Canada to treat malaria and rheumatic diseases Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). HCQ is available as a tablet that is usually taken two times per day. Doses up to 600mg per are used in clinical practice, but it is estimated that a dose of only 400mg daily, given as two doses of 200mg, will be sufficient to decrease the activity of microglia in patients with SPMS. HCQ is usually well tolerated.

Indapamide (IND) is a medication to treat high blood pressure that can reduce oxidative stress and improve the survival of nerve cells in laboratory studies. IND is currently approved to treat high blood pressure. IND is available in tablet form and is usually taken once a day, the most typical dose is 2.5mg. It is estimated that a dose of 2.5mg per day will be sufficient to treat oxidative stress in SPMS. IND is usually well tolerated.

Following a MinMax Simon-2-stage design, the study will require 35 patients with a complete 18 month follow-up. Presuming 20% drop-out, the investigators anticipate recruiting up to 42 patients. The trial will be conducted as follows: patients will continuously enter into the study until 35 patients have completed 18 months of follow-up with at least 75% adherence which will be measured by study drug count.

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