Osteoarthritis, Hip, Osteoarthritis, Knee
Conditions
Keywords
double blind randomised controlled trial, phase II, Devil's Claw, osteoarthritis of the knee, osteoarthritis of the hip
Brief summary
Osteoarthritis of both the knee and hip joints are common conditions; knee osteoarthritis affects 6% of adults over 30 years of age and osteoarthritis of the hip affects between 3% and 6% of the Caucasian population. Both forms of osteoarthritis are associated with disability. Conventional treatment (analgesics and the use non-steroidal anti-inflammatory, NSAIDS) is prophylactic, aimed at decreasing pain and improving function. However long term use of NSAIDS is associated with a high incidence of adverse events (gastrointestinal tract symptoms). A safer alternative treatment would therefore be beneficial. Both anecdotal evidence and recent studies have implicated the potential of the herbal remedy Devil's Claw (Harpagophytum procumbens) for the treatment of painful, chronic arthritic type conditions (Ernst and Chrubasik, 2000). Devil's Claw is an extract obtained from the root of the Harpagophytum procumbens plant, a member of the sesame family found in the Kalahari region in South Africa. It has been shown that this herbal remedy has anti-inflammatory and analgesic effects (Baghdikian et al, 1997). Currently Devil's Claw is marketed for use as a supportive treatment of degenerative arthrosis, is not a Medicines Control Agency licensed product and is freely available to the general public in health food stores and pharmacies. The objectives of this study are to assess the efficacy, optimum dosage and safety of the herbal remedy Devil's Claw (Harpagophytum) in the treatment of osteoarthritis of the knee and/or hip. The primary objective of this study is to investigate the following three principal questions: 1. To compare the efficacy of Devil's Claw with placebo in the treatment of osteoarthritis of the knee and/or hip 2. To determine the optimum dose of Devil's Claw and 3. To evaluate the safety and tolerability of three doses of Devil's Claw in the treatment of osteoarthritis of the knee/hip and to compare them to placebo There are also a number of secondary research objectives that will also be addressed (see later). These objectives are based on the following hypotheses : Hypotheses * Devil's Claw has anti-inflammatory properties (as assessed by the reduction in pain, stiffness and disability aspects on the WOMAC) in chronic osteoarthritis of the knee and/or hip after 16 weeks of treatment, as compared to placebo. * A dose response effect exists in the treatment of osteoarthritis of the knee/hip by Devil's Claw.
Detailed description
STUDY DESIGN: Randomized, placebo-controlled, dose-ranging two-centre study PREPARATIONS FOR INVESTIGATION: Devil's Claw (Allya®)/placebo as tablets STATISTICAL METHODS: Analysis on an intention to treat basis. The following tests will be performed and all statistical significance will be set at p \< 0.05: Primary efficacy analysis: The primary outcome will be the reduction in WOMAC total score from baseline to week 16. The week 16 means for the four treatment groups will be compared using an analysis of covariance taking account of baseline assessments and any demographic differences, age, gender, etc, which are found to be significant. Multiple comparison tests will be used to examine specific differences of initially specified interest, such as the two highest doses of Devil's Claw versus placebo. Secondary Efficacy Analysis: Similar analyses of covariance will be used to examine treatment group differences at week 16 compared with baseline for WOMAC subscales (pain, stiffness and physical function), and Quality of Life assessments (SF-36). Changes in the subject's well-being and overall global assessment will be compared using appropriate non-parametric tests, e.g. Mann-Whitney test or MacNemar's test. Changes in attitudes and health beliefs to CAM will be assessed using Chi-Squared tests. Safety Evaluation: Group differences between adverse event reporting will be assessed by descriptive methods. NUMBER OF PATIENTS: 264 (50 patients in each group, with an expected total of 64 drop-outs) NUMBER OF SITES: 2 TIME SCHEDULE: Study Start: April 2004 Study End: March 2007 Observation period/patient: 20 weeks
Interventions
DRUGDevil Claw
Dose ranging study so will elucidate dose Frequency is four times daily
DRUGPlacebo
Placebo has same dosing freq as for active intervention and for same time period
Sponsors
Pascoe Pharmazeutische Praeparate GmbH
University of Southampton
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with either a pragmatic diagnosis of osteoarthritis of the knee, with no other known rheumatological condition and who report the following clinical features (based on the ACR classification for knee OA1): * knee pain on most days of the previous month * morning stiffness of less than 30 minutes duration * stiffness in resting the joint and and are aged over 40 years * osteoarthritis of the hip, with no other known rheumatological condition and who report the following clinical features (based on the ACR classification for hip OA2): * hip pain on most days of the previous month and at least two of the following 3 features: * ESR \< 20mm/hour * Radiographic femoral or acetabular osteophytes * Radiographic joint space narrowing (superior, axial and/or medial) * And are aged over 45 years of age * The diagnosis of osteoarthritis will be confirmed by X-ray. Only patients who have grade 2 to 4 of the Kellgren and Lawrence scale will be recruited. (The Kellgren and Lawrence scale ranges from grade 0 to grade 4 where grades 0 and 1 represent doubtful osteoarthritic changes and therefore a doubtful diagnosis.) * Patients who have been on stable medication (conventional or complementary, including nutritional medicine) for the past three months, but are still getting symptoms (incomplete responders) * Only those patients who record baseline pain scores on the WOMAC scale of at least 20 mm on the VAS for a minimum of 6 out of 7 days monitored during the period from Clinic Visit 1 (screening) and Clinic Visit 2 (baseline) * Ability to comply with the requirements of the study and to give informed consent * For women of child-bearing potential: negative pregnancy test
Exclusion criteria
* Participation in an investigational trial within 30 days prior to enrollment * Previous treatment with Devil' s Claw within 90 days prior to enrollment * Patients awaiting a replacement knee or hip joint * Patients with other conditions that cause pain * Patients with congenital dislocation of the hip * Patients who have had operations on their hip due to previous trauma * Patients with severe co-morbidities - including severe cardiac or pulmonary disease and cancer * Dementia, psychoses, or other significant impairment of mental status that would prohibit sufficient comprehension, provision of informed consent and to allow undertaking of the necessary self-care or toxicity reporting * Patients taking corticosteroid medication * Known allergies against any of the ingredients of the treatments * Patients who would be unable to complete the self assessment forms, or to attend for X-ray and clinical examination * Patients with other known rheumatic disease such as rheumatoid arthritis * Patients with the diagnosis gout * Patients who report a red or hot swollen joint (which is unlikely to be due to OA), and would require further rheumatological assessment * Patients with conditions known to be contraindicated to the study medication i.e. patients with gastric or duodenal ulcers; gallstones; patients taking drugs for arrhythmias; patients with heart failure * Patients who are pregnant, trying to become pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Western Ontario and Mc Master University OA Index (WOMAC) | Baseline, week 8 and week 16 | WOMAC is a disease specific outcome measure for osteoarthritis. It has three subscales assessing pain (5 questions), stiffness (2 questions) and function (15 questions). together the subscales give an overall total score ranging from 0 (worst) to 100 (best; an increase in total score indicates an improvement in health. THe outcome was measured at baseline, week 8 and week 16. In this study the primary outcome was the reduction in WOMAC total score from baseline to the end of treatment at week 16. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disability Subscale on The Western Ontario and Mc Master University OA Index | baseline, 8 and 16 weeks | Subscale assessed by 100mm VAS based on twelve questions addressing disability in osteoarthritis with a higher score indicating worse symptoms. The VAS used terminators of no disability (0mm) to extreme disability (100mm). The measure was recorded at baseline, week 8 and week 16. We reported the outcome as the change from baseline to end of treatment at week 16. |
| Stiffness Subscale on the The Western Ontario and Mc Master University OA Index | Baseline, week 8 and week 16 | Subscale assessed by 100mm VAS based on two questions addressing stiffness in osteoarthritis;a higher score indicating worse symptoms. The VAS used terminators of no stiffness (0mm) to extreme stiffness (100mm). The measure was recorded at baseline, week 8 and week 16. We reported the outcome as the change from baseline to end of treatment at week 16. |
| Short Form-36 (SF-36) | Baseline, week 8 and week 16 | Quality of Life assessment containing 8 scales clustered into 2 summary scales: physical health and mental health. Each question is scored out from 0 (indicating worst health) to 100 (indicating best health). Mean scores for the 8 scales (total scores/no questions completed) are calculated to give a total score for each of the two summary scales between 0 (worst health) and 100 (best health). SF36 was recorded at baseline, week 8 and at the end of treatment at week 16. we reported the change from baseline to end of treatment as the outcome. |
| Pain Subscale on Western Ontario and Mc Master University OA Index | Baseline, week 8 and week 16 | Subscale assessed by 100mm VAS based on five questions addressing pain in osteoarthritis using the terminators no pain (0mm) to extreme pain (100mm). a higher score therefore indicates more severe pain. This outcome was recorded at baseline, week 8 and week 16 (end of treatment). The outcome for this study was reported as the change in WOMAC pain score from baseline to end of treatment at week 16. |
| Complementary and Alternative Medicine Beliefs Inventory | four monthly | Questionnaire to assess changes in attitudes and health beliefs to CAM.the questionnaire as 17 questions, each scored on a 7 point likert scale from strongly disagree to strongly agree; a higher score indicates stronger belief in the measure. Minimum score 17, maximum score 119 |
| Adverse Event Reporting | Baseline and weeks 2,4,6,8,12 and 16 | To identify Group differences between the number of adverse event recorded by patient for both serious and non serious adverse events, as well as events considered being attributable to the study medication. |
| Patient Global Assessment | Baseline, week 8 and week 16 | To assess changes in the subject's well-being based on 7 point likert scale ranging from very poor (0 point) to very good (7 point). Outcome was recorded at baseline, week 8 and end of treatment at week 16. We reported outcome as the change in patient global assessment from baseline to end of treatment at week 16. |
Countries
United Kingdom
Participant flow
Recruitment details
Recruited during 2004 to 2007 Recruitment location: From GP clinics and from adverts in the media
Pre-assignment details
Patients attended screening clinic to confirm diagnosis of osteoarthritis of the knee (grade 2-4) by clinical examination and X ray and ensure other entry criteria met i.e.baseline pain (at least 20mm on 100mm scale over 6 of 7 days between screening and baseline)and exclude any other condition causing knee pain.
Participants by arm
| Arm | Count |
|---|---|
| 240mg Devil Claw Total daily dose was 240mg/day taken orally; this dose is suboptimal. Patients allocated to this treatment arm receiving eight tablets split into two doses to take daily for 16 weeks. of these eight tablets, 7 were placebo medication and one was active Devil Claw (the active tablet contained 240mg Devil Claw). | 15 |
| 960mg/d Devil Claw total daily dose was 960mg/day taken orally. Patients allocated to this treatment arm receiving eight tablets split into two doses to take daily for 16 weeks. of these eight tablets, 4 were placebo medication and four were active Devil Claw, with each active tablet containing 240mg Devil Claw . | 19 |
| 1,920mg/d Devil Claw total daily dose was 1920mg/day of Devil claw taken orally. Patients allocated to this treatment arm receiving eight tablets split into two doses to take daily for 16 weeks. All eight tablets contained active Devil Claw; each active tablet containing 240mg Devil Claw . | 16 |
| Placebo total daily dose was 0mg/day of Devil Claw. Patients allocated to this treatment arm receiving eight tablets split into two doses to take daily for 16 weeks. of these eight tablets, all were placebo medication. tablets were taken orally. | 17 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Other | 0 | 2 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | 960mg/d Devil Claw | 1,920mg/d Devil Claw | 240mg Devil Claw | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 5 Participants | 9 Participants | 8 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 11 Participants | 6 Participants | 9 Participants | 39 Participants |
| Age Continuous | 59.6 years STANDARD_DEVIATION 6.9 | 59.8 years STANDARD_DEVIATION 8.4 | 65.2 years STANDARD_DEVIATION 11.9 | 63.2 years STANDARD_DEVIATION 8.6 | 61.8 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment United Kingdom | 19 participants | 16 participants | 15 participants | 17 participants | 67 participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 5 Participants | 9 Participants | 32 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 10 Participants | 8 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 15 | 18 / 19 | 15 / 16 | 16 / 17 |
| serious Total, serious adverse events | 0 / 15 | 1 / 19 | 0 / 16 | 0 / 17 |
Outcome results
Primary
Western Ontario and Mc Master University OA Index (WOMAC)
WOMAC is a disease specific outcome measure for osteoarthritis. It has three subscales assessing pain (5 questions), stiffness (2 questions) and function (15 questions). together the subscales give an overall total score ranging from 0 (worst) to 100 (best; an increase in total score indicates an improvement in health. THe outcome was measured at baseline, week 8 and week 16. In this study the primary outcome was the reduction in WOMAC total score from baseline to the end of treatment at week 16.
Time frame: Baseline, week 8 and week 16
Population: Zero participants were analysed as the study was terminated prematurely.
Secondary
Adverse Event Reporting
To identify Group differences between the number of adverse event recorded by patient for both serious and non serious adverse events, as well as events considered being attributable to the study medication.
Time frame: Baseline and weeks 2,4,6,8,12 and 16
Population: Zero participants were analysed as the study was terminated prematurely
Secondary
Complementary and Alternative Medicine Beliefs Inventory
Questionnaire to assess changes in attitudes and health beliefs to CAM.the questionnaire as 17 questions, each scored on a 7 point likert scale from strongly disagree to strongly agree; a higher score indicates stronger belief in the measure. Minimum score 17, maximum score 119
Time frame: four monthly
Population: Zero participants were analysed as the study was terminated prematurely
Secondary
Disability Subscale on The Western Ontario and Mc Master University OA Index
Subscale assessed by 100mm VAS based on twelve questions addressing disability in osteoarthritis with a higher score indicating worse symptoms. The VAS used terminators of no disability (0mm) to extreme disability (100mm). The measure was recorded at baseline, week 8 and week 16. We reported the outcome as the change from baseline to end of treatment at week 16.
Time frame: baseline, 8 and 16 weeks
Population: Zero participants were analysed as the study was terminated prematurely
Secondary
Pain Subscale on Western Ontario and Mc Master University OA Index
Subscale assessed by 100mm VAS based on five questions addressing pain in osteoarthritis using the terminators no pain (0mm) to extreme pain (100mm). a higher score therefore indicates more severe pain. This outcome was recorded at baseline, week 8 and week 16 (end of treatment). The outcome for this study was reported as the change in WOMAC pain score from baseline to end of treatment at week 16.
Time frame: Baseline, week 8 and week 16
Population: Zero participants were analysed as the study was terminated prematurely.
Secondary
Patient Global Assessment
To assess changes in the subject's well-being based on 7 point likert scale ranging from very poor (0 point) to very good (7 point). Outcome was recorded at baseline, week 8 and end of treatment at week 16. We reported outcome as the change in patient global assessment from baseline to end of treatment at week 16.
Time frame: Baseline, week 8 and week 16
Population: Zero participants were analysed as the study was terminated prematurely
Secondary
Short Form-36 (SF-36)
Quality of Life assessment containing 8 scales clustered into 2 summary scales: physical health and mental health. Each question is scored out from 0 (indicating worst health) to 100 (indicating best health). Mean scores for the 8 scales (total scores/no questions completed) are calculated to give a total score for each of the two summary scales between 0 (worst health) and 100 (best health). SF36 was recorded at baseline, week 8 and at the end of treatment at week 16. we reported the change from baseline to end of treatment as the outcome.
Time frame: Baseline, week 8 and week 16
Population: Zero participants were analysed as the study was terminated prematurely.
Secondary
Stiffness Subscale on the The Western Ontario and Mc Master University OA Index
Subscale assessed by 100mm VAS based on two questions addressing stiffness in osteoarthritis;a higher score indicating worse symptoms. The VAS used terminators of no stiffness (0mm) to extreme stiffness (100mm). The measure was recorded at baseline, week 8 and week 16. We reported the outcome as the change from baseline to end of treatment at week 16.
Time frame: Baseline, week 8 and week 16
Population: Zero participants were analysed as the study was terminated prematurely.