Timed Release Tablet Prednisone in Polymyalgia Rheumatica

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2011 by University Hospitals Bristol NHS Trust.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by:
University Hospitals Bristol NHS Trust
ClinicalTrials.gov Identifier:
NCT00836810
First received: February 2, 2009
Last updated: August 4, 2011
Last verified: August 2011
  Purpose

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. The joints are not affected by this disease.

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.


Condition Intervention Phase
Polymyalgia Rheumatica
Drug: Timed Release Tablet Prednisone
Drug: Prednisolone
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Circadian Variation in Cytokines and the Effect of Timed Release Tablet Prednisone in Polymyalgia Rheumatica

Resource links provided by NLM:


Further study details as provided by University Hospitals Bristol NHS Trust:

Primary Outcome Measures:
  • Peak serum IL-6 concentration [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    As measured from (approximately) hourly blood sampling over 24 hours


Secondary Outcome Measures:
  • Morning stiffness (minutes) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    How long was your morning stiffness today?

  • Pain (severity) [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    100mm visual analogue scale. Question: How much pain have you had in the last 24 hours? Anchors: No pain; Severe pain.

  • Patient's opinion of condition [ Time Frame: Current ] [ Designated as safety issue: No ]
    100mm visual analogue sacale. Question: Considering all the ways your pain and/or stiffness affect(s) you, please mark on the line how well you are doing. Anchors: Very well; Very badly.

  • Clinician's opinion of disease activity. [ Time Frame: Current ] [ Designated as safety issue: No ]
    100mm visual analogue scale. Question: Clinician's opinion of disease activity. Anchors: None; Severe

  • PMR Disease Activity Score [ Time Frame: Current ] [ Designated as safety issue: No ]
    Numerical value of: CRP (mg/dl) + Patient's opinion of condition (mm) + Clinician's opinion of condition (mm) + morning stiffness (min x 0.1) + Elevation of upper limb (0-3 scale).

  • Serum cortisol [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
    Measurement of circadian change in serum cortisol in (approximately) hourly blood samples

  • Disability (HAQ) [ Time Frame: Past week ] [ Designated as safety issue: No ]
    Health Assessment Questionnaire Disability Index

  • Fatigue (BRAF - MDQ) [ Time Frame: One week ] [ Designated as safety issue: No ]
    Bristol Rheumatoid Arthritis Fatigue Multi Dimensional Questionnaire


Estimated Enrollment: 24
Study Start Date: October 2009
Estimated Study Completion Date: December 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TRT Prednisone
12 patients will be taking night time TRT prednisone at a dose of 7mg a day over 2 weeks.
Drug: Timed Release Tablet Prednisone
Dose: 7mg, taken at 10pm every night for 2 weeks in the form of oral tablets.
Other Name: Lodotra
Active Comparator: Standard Prednisolone
12 patients will be taking morning Prednisolone at a dose of 7mg over 2 weeks.
Drug: Prednisolone
Dose: 7mg, taken in the morning for 2 weeks in the form of oral tablets.

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.

  Eligibility

Ages Eligible for Study:   50 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of PMR by standard criteria. The Bird criteria will be used. 3 or more features are required to make the diagnosis.

    • Bilateral shoulder pain/stiffness
    • Duration of symptoms <2/52
    • Initial ESR >40 mm/h
    • Stiffness >1 h
    • Age >65 years
    • Depression and/or weight loss
    • Bilateral upper arm tenderness
  • Are over 50 but less than 85 years old.
  • No or stable NSAID or analgesic therapy for at least 7 days.
  • Currently active disease defined by a CRP at least 10mg/L, ESR at least 29mm in one hour or PV >1.72

Exclusion Criteria:

  • Currently on oral glucocorticoid treatment or taken within 2 months
  • Parenteral glucocorticoid treatment with the last 2 months
  • Pregnancy and lactation
  • Inflammatory diseases such as inflammatory bowel disease, colitis, asthma
  • Co-existent giant cell arteritis
  • Other auto-immune diseases
  • Cancer
  • Infections, treatment with antibiotics within the past 6 weeks
  • Significant renal disease (creatinine >150 μmol/L)
  • Significant hepatic impairment
  • Participation in a clinical trial within the past 30 days
  • Working shift employee
  • Jet lag
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00836810

Locations
United Kingdom
University Hospitals Bristol NHS Trust
Bristol, Avon, United Kingdom, BS2 8HW
Sponsors and Collaborators
University Hospitals Bristol NHS Trust
Investigators
Principal Investigator: John R Kirwan, MBBS,MD,FRCP University Hospitals Bristol NHS Trust
  More Information

No publications provided

Responsible Party: Prof. John R Kirwan, University Hospitals Bristol
ClinicalTrials.gov Identifier: NCT00836810     History of Changes
Other Study ID Numbers: ME/2008/3031
Study First Received: February 2, 2009
Last Updated: August 4, 2011
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University Hospitals Bristol NHS Trust:
Circadian variations of cytokines in PMR
effect of TRT Prednisone in cytokines

Additional relevant MeSH terms:
Polymyalgia Rheumatica
Giant Cell Arteritis
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Vasculitis, Central Nervous System
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Arteritis
Vascular Diseases
Cardiovascular Diseases
Vasculitis
Skin Diseases, Vascular
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Methylprednisolone acetate
Prednisolone acetate
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisone
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 20, 2014