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Published on: September 12, 2016
Hydroxychloroquine for Primary Progressive Multiple Sclerosis
Marcus W Koch1,2, Sharanjit Kaur1, Kayla Sage1
1Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Objective:
Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro.
Methods:
We conducted a single-arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was ≥20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up.
Results:
Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2-stage design to compare a null hypothesis of 40% of the cohort worsening against the one-sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well-tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use.
Interpretation:
HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940-948.
Insights
Hydroxychloroquine (HCQ) shows promise for treating primary progressive multiple sclerosis (PPMS) by reducing disability worsening. Further clinical trials are recommended for this neuroprotective drug.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Primary progressive multiple sclerosis (PPMS) is challenging to treat with current immunomodulatory or immunosuppressive therapies.
- Chronic microglial activation is a key factor in PPMS pathophysiology.
- Hydroxychloroquine (HCQ), an antimalarial drug, demonstrates in vitro neuroprotective effects and reduces human microglial activity.
Purpose of the Study:
- To evaluate the efficacy of hydroxychloroquine (HCQ) in reducing disability worsening in patients with PPMS.
- To assess HCQ as a potential treatment for PPMS, particularly in the absence of overt focal inflammation.
Main Methods:
- A single-arm, phase II futility trial involving 35 participants treated with 200 mg oral HCQ twice daily for 18 months.
- Exclusion of participants with contrast-enhancing lesions on MRI to focus on disability worsening without overt inflammation.
- Primary endpoint: ≥20% worsening on the timed 25-foot walk between 6 and 18 months, analyzed using a Simon 2-stage design.
Main Results:
- The study met its primary endpoint, with only 8 out of 35 participants experiencing clinically significant worsening (less than the expected 40%).
- HCQ was generally well-tolerated, with 82% reporting adverse events and 12% reporting serious adverse events, most unlikely related to HCQ.
- The observed rate of worsening (22.8%) was significantly lower than the 40% null hypothesis threshold.
Conclusions:
- Hydroxychloroquine (HCQ) treatment was associated with reduced disability worsening in individuals with primary progressive multiple sclerosis (PPMS).
- HCQ presents a promising therapeutic candidate for PPMS and warrants further investigation in randomized controlled trials.
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