A Phase 4, Randomized-withdrawal, Double-blind,Placebo-controlled, Parallel-group Study to Investigate the Clinical Benefit of Midodrine Hydrochloride in Male and Female Subjects with Symptomatic Orthostatic Hypotension.
This is a randomized withdrawal study in patients wtih SOH who are already on Midodrine to assess the benefit of Midodrine on orthostatic hypotension. After initial screening evaluation after withdrawal from midodrine, those patients who has significant orthostatic symptoms when off Midodrine will be either placed on Placebo or Midodrine in blinded fashion. These steps are performed in an inpatient research center to minimize risk to patient. Primary Endpoint: The primary endpoint for each randomized subject is defined as failure to maintain a response (Yes/No). Any randomized subject that meets both the first 2 criteria below on Day 17, or satisfies the 3rd criterion, will be considered to have failed to maintain a response:
* The Part C post-baseline Orthostatic Hypotension Symptom Assessment (OHSA) item 1 score increases by ≥4 compared to the baseline OHSA item 1 score (Day -1). A copy of the OHSA scale can be found in Appendix 2.
* Urine pregnancy test may be carried out on Day -2 or prior to dosing and orthostatic assessments on Day -1
* There is an increase in the number of syncopal/near syncopal events or severity of events compared to those observed at baseline (Day -1)
* If the subject experiences severe symptoms or adverse events (AEs) during Part C eg, unable to get out of bed or carry out basic activities of daily living, (this may be reported by the subject, but must be confirmed by the Investigator) and is, therefore, unable to stand in order for the above assessments to be conducted .In addition, any subject who withdraws during the double-blind randomized-withdrawal phase (Part C) will be considered as having failed to maintain a response.
* Blinded dosing (Part C) will use capsule formulation (over-encapsulated tablets)
* Open-label dosing will use 2.5 and 10mg tablets.
Secondary Endpoint: Safety:
Safety will be assessed by AEs, clinical laboratory tests, vital signs (systolic and diastolic BP,
pulse, body temperature, and respiratory rate), discontinuations, physical examination findings, and ECGs.
1. Male and female subjects must be 18 years of age or older and ambulatory (when receiving adequate therapy for their SOH).
2. Females of child-bearing potential (FOCP) must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test. These females should abstain from sexual activity that could result in a pregnancy, or agree to use acceptable contraceptives throughout the period of the entire study and for 30 days after the last dose of investigational product.
3. A documented history of severe SOH (eg, due to Parkinson’s disease, Shy-Drager syndrome, multiple system atrophy, pure autonomic failure, or autonomic neuropathies) that, in the judgment of the treating physician, has required treatment with midodrine HCl, and has been at a stable dose for at least 3 months.
4. The subject has manifested at least 1 of the following symptoms while standing or had a medical history of 1 of the following when not treated for orthostatic hypotension (OH): dizziness, lightheadedness, feeling faint, or feeling like they might black out.
5. The subject is willing and able to undergo the procedures required by the protocol, including inpatient stay as required, assessment completion, protocol compliance, and participation in the placebo dosing period(s).
6. The subject has adequate hydration status (as assessed by physical examination and clinical laboratory parameters, eg, urine specific gravity).
7. Ability to provide written, signed, and dated informed consent to participate in the study.