Evaluating the Use of Oral Indapamide to Reduce Disabiltiy Progression in Progressive Multiple Sclerosis (MS)

Finding an effective treatment for progressive multiple sclerosis (PMS) is one of the greatest challenges and unmet needs in MS research. Despite the many anti-inflammatory therapies currently available, about 2-3 percent of people with relapsing-remitting MS (RRMS) convert to secondary progressive MS (SPMS) per year. Around 10 to 15 percent of people with MS suffer from primary progressive MS (PPMS). In both forms of PMS, disability worsening occurs steadily, unrelentingly, and independent of relapses.

Comparative pathological studies show that PMS differs from RRMS in several important aspects: active demyelinating lesions are frequent in RRMS but infrequent in PMS, while neurodegeneration, cortical lesions, and slowly expanding white matter lesions all are more prominent in PMS compared to RRMS. Underlying this, in PMS there is more oxidative tissue injury, mitochondrial dysfunction, and diffuse neurodegeneration. Oxidative tissue injury is a key pathophysiological factor implicated in PMS, and other chronically progressive neurological diseases. Reactive oxygen and nitrogen species are elevated, and cause oxidative damage to organelles such as mitochondria in MS. In-vitro experiments have found that the generic antihypertensive drug indapamide (IND) has a very powerful antioxidant, as well as neuroprotective effect in in-vitro experiments. We hypothesize that treating people with PMS with IND can reduce the worsening of disability in PMS.

This study is a phase 2 futility trial with a single intervention arm using a Simon Two-Stage futility design. We will include up to 42 participants with PPMS and up to 42 participants with SPMS who will be followed for 12 months.

We will include people with PPMS and SPMS aged 18 to 65 years, with a screening EDSS score of 4.0 to 6.5 inclusive. We will include participants with a screening T25FW of 5 seconds or more if they have PPMS, and with 9 seconds or more if they have SPMS, based on slightly different progression speeds. Exclusion criteria are known contra-indications to indapamide, pregnancy and breast-feeding in women, and specific co-medications.

The primary outcome will be disability worsening, defined as a >=20% worsening on the timed 25 foot walk (T25FW) at month 12 compared to the baseline measurement (without confirmation). The primary outcome measure will be assessed at screening, at baseline, and at 1, 6, and 12 months of follow-up. Secondary outcome measures include the Expanded Disability Status Scale, Symbol Digit Modalities Test, and patient reported outcomes of fatiguiability and quality of life.

Trial participants will be treated with 2.5mg IND once daily day for 12 months, with study visits at baseline, 2 weeks, 1 month, and 3, 6, 9, and 12 months. An interim futility analysis will determine whether the trial will continue or stop prematurely. Once 13 patients with PPMS and 13 patients with SPMS have completed the full 12 month follow up with sufficient adherence to medication. If 5 out of the 13 in each group have experienced a significant worsening of the T25FW indapamide treatment in PMS will be deemed futile, and the trial will be stopped, as the rate of progression is then sufficiently similar to historical data of untreated PMS patients.

During the trial safetly labs will be drawn and ECGs will be made to ensure the safety of the trial participants.

Inclusion criteria

• Written informed consent obtained
• Aged between 18 and 65 years
• Diagnosed with PPMS or SPMS, according to current diagnostic criteria
• Screening Expanded Disability Status Scale score between 4.0 and 6.5 inclusive.
• Screening T25FW (average of two trials) of 5 seconds or more for people with PPMS, or of 9 seconds or more for people with SPMS
• Use of effective methods of contraception for women of childbearing potential.

Exclusion criteria

• Individuals with renal insufficiency and an eGFR below 30ml/min per 1.73 m2
• Individuals with a blood pressure below 110 mmHg systolic or 70 mmHg diastolic
• Individuals with significant hepatic impairment (pre-existing or developing during the trial)
• Individuals with clinically significant abnormal screening labs
• Individuals with cardiac arrhythmia
• Individuals with a prolonged QT interval: individuals with frequency corrected QT (QTc) intervals of more than 450ms (men) or 470ms (women) at the screening examination will not be included in the study, and participants with QTc intervals of greater than 500ms on any of the other ECG examinations throughout the study will be excluded from the study.
• Individuals who are pregnant or currently breast-feeding
• Individuals with an allergy or other intolerability to IND
• Individuals who use Fampridine or 4-aminopyridine
• Individuals who start Fampridine or 4-aminopyridine during the trial
• Individuals who start Baclofen or Tizanidine during the trial
• Individuals who increase the dose of Baclofen or Tizanidine during the trial
• Individuals who receive treatment with Botulinum toxin in the leg muscles during the trial
• Individuals who use siponimod, ocrelizumab, natalizumab or other disease-modifying treatment for RRMS
• Individuals with recent gadolinium enhancement or new T2 lesions on brain/spinal cord MRI in the 6 months prior to inclusion
• Concomitant use of corticosteroids