Timed Release Tablet Prednisone in Polymyalgia Rheumatica
Condition: Polymyalgia Rheumatica
MeSH terms: Polymyalgia Rheumatica; Giant Cell Arteritis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Polymyalgia Rheumatica (PMR) is a disease that usually affects older people. Patients
      complain of stiffness and pain around the shoulders and hips. The stiffness is more severe in
      the morning.

      Research in Rheumatoid Arthritis (RA), which is also much worse in the mornings, has shown
      that IL-6 (a chemical messenger) peaks in the morning with very low levels in the evening.
      This may explain why stiffness is most severe in the morning. The investigators have recently
      shown that timed release tablet (TRT) prednisone reduced morning IL-6 levels close to normal
      in RA patients.

      In PMR, IL-6 levels are high. Given that both RA and PMR have the same variation of symptoms
      (worse in the morning); it's likely that PMR patients have the same variation in IL-6 levels.
      In a pilot study of 4 patients conducted within our department, IL-6 levels did, indeed, show
      a pattern similar to that found in RA patients, but the number of patients is small and the
      results need to be confirmed.

      PMR is treated with moderate doses of glucocorticoid for about 2 years. While generally
      abolishing symptoms, these doses are very likely to cause adverse effects such as high blood
      pressure, weight gain and diabetes. These side effects are much less frequent when lower
      doses are used but these are not sufficient to control PMR using traditional dosing regimes.

      Therefore, the investigators wish to investigate whether TRT prednisone in PMR will reduce
      IL-6 and morning symptoms similar to those in RA. The investigators think that it will do so,
      and will achieve symptomatic relief at a lower dose. If this is the case, then treating
      patients with lower doses may mean reduced risk of glucocorticoid induced side effects in the
      future.

      Patients will be recruited through the outpatient clinics at the University Hospitals
      Bristol, NHS Foundation Trust, Rheumatology Centre. Each patient will give fully informed
      consent after being given details of the study and a patient information sheet. The research
      doctor will take the consent 2-5 days after this information has been provided and with the
      presence of a witness. The study will consist of the collection and analysis of sequential
      blood samples over a 24 hour period on 2 occasions 2 weeks apart, taking TRT prednisone 7 mg
      / standard release prednisolone 7 mg for the intervening period. The investigators will aim
      to recruit 12 patients in each arm. A single blood sample will be taken when the patient
      comes for a routine review 2 weeks later.
    

Detailed description: 
      The volunteers will stay overnight in the Rheumatology Centre; 24-hour Research Facility on
      two occasions (Night A and Night B) 12-16 days apart. This slight flexibility will allow some
      leeway in arranging residency nights. In general the investigators will aim for 14 days.
      After Night A, each volunteer will be randomized (in pre-prepared sealed envelopes) to take
      one tablet morning or evening. Half the patients will take active standard release
      prednisolone in the morning. The other half will receive active TRT Prednisone 7mg to be
      taken each evening at 22:00 until the day after Night B. All study medication will then be
      discontinued and standard therapy (prednisolone 15mg each morning) commenced. Patients will
      be reviewed after 2 weeks to ensure expected clinical response and to measure IL-6 and other
      cytokines in the blood sample that is also needed to check the acute phase response.

      On Night A and Night B, volunteers will attend the Rheumatology Centre at 15:00.

      First, standard assessment tools will be used by the research doctor to assess the state of
      the patient's condition.

      These assessments will be:

        -  Morning stiffness (minutes)

        -  Pain (visual analogue scale)

        -  Patient's opinion of condition

        -  Clinician's opinion of condition

        -  Health Assessment Questionnaire

        -  BRAF-MDQ fatigue scale and the Hospital Anxiety and Depression Scale.

      An intravenous (IV) cannula will be inserted into the elbow area. At least one hour after the
      IV cannula is placed, but usually at 16:30, a blood sample (2ml) will be taken through the IV
      cannula and the cannula flushed. At 22:30 the main lights will be switched off and the
      volunteer encouraged to sleep. In total, 20 samples will be taken from the cannula over 24
      hours.

      The investigators will calculate mean and standard deviation (or non-parametric analysis if
      the data are not normally distributed) for blood cytokines for each time point. These mean
      and standard deviations will be compared for pre- and post-TRT prednisone samples.
    

Intervention name(s): Timed Release Tablet Prednisone; Prednisolone
Intervention type(s): Drug; Drug
Intervention description(s): Dose: 7mg, taken at 10pm every night for 2 weeks in the form of oral tablets.; Dose: 7mg, taken in the morning for 2 weeks in the form of oral tablets.
Other intervention name(s): Lodotra
Intervention MeSH terms: Prednisone; Prednisolone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Circadian variations of cytokines in PMR; effect of TRT Prednisone in cytokines