Remote Ischemic Conditioning in PPMS

Progressive MS remains the most difficult therapeutic challenge. Remyelination is a promising therapeutic strategy but an effective pharmacologic intervention remains elusive. Remote ischemic conditioning (RIC) is a non-pharmacologic intervention that has been studied in the context of stroke, where transient limb ischemia leads to neuroprotection. However, RIC has not yet been studied in MS. The investigators hypothesized that repeating RIC over several days may induce molecular/cellular changes in the CNS that promote remyelination. Since RIC is safe, tolerable and ready for clinical translation (recent stroke trials have shown promise), the investigators will run a clinical study to test RIC in people with primary progressive MS.

The purpose of this clinical trial is to determine if RIC in a dose of 4 cycles daily can prevent worsening of walking ability in people PPMS. The trial is funded through MS Canada as well as a private donation to the Hotchkiss Brain Institute MS Translational Clinical Trials Research Program and the University of Calgary. There is no sponsorship from the pharmaceutical industry.

Remote Ischemic conditioning (RIC): Ischemic-preconditioning entails inducing short periods of cyclical tissue ischemia that confers subsequent protection against ischemia-reperfusion-injury. The rationale is that short periods of ischemia do not cause irreversible injury, but instead induce an endogenous protective environment. This short period of ischemia is not injurious, and it triggers endogenous protective signals (such as anti-inflammatory and antioxidant molecules) that reach distant organs, such as the heart, liver or the CNS. As an endogenous, non-specific response, the mechanisms involved in RIC are complex and include inflammation, oxidative stress, changes in endothelial function, cell survival etc.

Current treatments for progressive Multiple Sclerosis (the immune-modulators Siponimod and Ocrelizumab) are only modestly effective and primarily benefit people with active inflammatory disease activity (recent relapses and/or enhancing lesions on MRI). Progression free of inflammatory activity is characterized by slow accumulation of disability, greatly affecting quality of life in people with Multiple Sclerosis (MS). The investigators believe RIC is ideally suited to be tested as a therapy for progression in MS. Recent clinical trials in vascular disease have shown that daily RIC can be performed for up to a year and suggested an all-cause mortality benefit. In a recent (RICAMIS trial, 2022) multicenter, randomized trial of people with acute ischemic stroke (\> 1,000 participants), 14-day RIC treatment led to improved functional outcomes at 6-months. No serious side effects were reported, and tolerability was good.

This important study was the first phase III trial to find a "protective" effect for RIC in neurological disease, and highlights the timeliness and potential for re-purposing RIC as a therapy for MS.

In this trial, the investigators will investigate whether RIC treatment can prevent disability worsening in people with Primary Progressive MS (PPMS).

The primary objective of this trial is to demonstrate non-futility of RIC for reducing progression of disability, as measured with the timed 25-foot walk (T25FW), in people with PPMS.

This is a phase II open-label, single-center, single-arm futility trial. The study will follow the Simon-2-stage MiniMax design for futility studies.

Eligibility Criteria:
Inclusion Criteria:

Written informed consent obtained

* Men and women aged of 18 and 65 years inclusive
* With Primary Progressive Multiple Sclerosis, according to current diagnostic criteria
* Screening Expanded Disability Status Scale score between 4.0 and 6.5 inclusive
* Screening timed 25-foot walk (average of two trials) of 5.5 seconds or more

Exclusion Criteria:

Patients whose screening MRI scan shows gadolinium enhancing lesions

* Patients with known renal insufficiency
* Patients with known significant hepatic impairment
* Patients with known allergy to gadolinium MRI contrast agent
* Patients currently using immune-modulators such as ocrelizumab or hydroxychloroquine
* Patients currently using therapeutic anticoagulation (blood thinners, such as warfarin, apixaban, rivaroxaban, dabigatran, enoxaparin)
* Patients currently using Fampridine or 4-aminopyridine
* Patients planning to start Fampridine or 4-aminopyridine during the study period
* Patients planning to start Baclofen or Tizanidine during the duration of the study
* Patients who increase the dose of Baclofen or Tizanidine during the study period
* Patients who receive treatment with Botulinum toxin in the leg muscles during the study period
* Patients who are unable or unwilling to undergo gadolinium enhanced MRI scans
* Patients with known history of thrombotic events in the upper extremities