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unexpected withdrawal of funding
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| Name | Class |
|---|---|
| Pascoe Pharmazeutische Praeparate GmbH | INDUSTRY |
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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:
These objectives are based on the following hypotheses :
Hypotheses
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 240mg Devil claw | Experimental | Sub clinical dose if the 3 doses employed |
|
| 960mg Devil Claw | Experimental | Active dose |
|
| 1920 mg Devil claw | Experimental | Active dose |
|
| Placebo | Placebo Comparator | Comparator for all active intervention arms |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Devil Claw | Drug | Dose ranging study so will elucidate dose Frequency is four times daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, week 8 and week 16 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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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):
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):
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:
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| Name | Affiliation | Role |
|---|---|---|
| George Lewith, MA MD FRCP | University of Southampton | Principal Investigator |
| Sarah Brien, Bsc Msc PhD | University of Southampton | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wellcome Trust Clinical Research Facility, Southampton General Hospital | Southampton | Hants | SO16 6YD | United Kingdom |
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.
Recruited during 2004 to 2007 Recruitment location: From GP clinics and from adverts in the media
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). |
| FG001 | 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 . |
| FG002 | 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 . |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Zero participants were analysed as the study was terminated prematurely. | Posted | Jun 2010 | Mean | Standard Deviation | Unit on 100mm scale | Baseline, week 8 and week 16 |
|
Twenty week period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Transient blindness | Eye disorders | MedDRA (10.1) | Systematic Assessment | Not related to study medication |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (10.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Sarah Brien | University of Southampton | 07870642667 | sbb@southampton.ac.uk |
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| ID | Term |
|---|---|
| D020370 | Osteoarthritis, Knee |
| D015207 | Osteoarthritis, Hip |
| ID | Term |
|---|---|
| D010003 | Osteoarthritis |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| C444600 | Harpagophytum extract LI 174 |
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|
| Placebo | Drug | Placebo has same dosing freq as for active intervention and for same time period |
|
| Baseline, week 8 and week 16 |
| 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. | baseline, 8 and 16 weeks |
| 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. | Baseline, week 8 and week 16 |
| 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. | Baseline, week 8 and week 16 |
| 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. | Baseline, week 8 and week 16 |
| 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 | four monthly |
| 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. | Baseline and weeks 2,4,6,8,12 and 16 |
| Withdrawal by Subject |
|
| Lost to Follow-up |
|
| Adverse Event |
|
| Other |
|
| 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 . |
| BG002 | 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 . |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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 . |
| OG002 | 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 . |
| OG003 | 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. |
|
| 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. | Zero participants were analysed as the study was terminated prematurely. | Posted | Mean | 95% Confidence Interval | Unit on 100mm VAS scale | Baseline, week 8 and week 16 |
|
|
| 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. | Zero participants were analysed as the study was terminated prematurely | Posted | Mean | 95% Confidence Interval | unit on 100mm VAS scale | baseline, 8 and 16 weeks |
|
|
| 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. | Zero participants were analysed as the study was terminated prematurely. | Posted | Mean | 95% Confidence Interval | Unit on 100mm VAS scale | Baseline, week 8 and week 16 |
|
|
| 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. | Zero participants were analysed as the study was terminated prematurely. | Posted | Mean | 95% Confidence Interval | Unit of scale | Baseline, week 8 and week 16 |
|
|
| 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. | Zero participants were analysed as the study was terminated prematurely | Posted | Jun 2010 | Mean | 95% Confidence Interval | Unit on scale (Likert from very poor to | Baseline, week 8 and week 16 |
|
|
| 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 | Zero participants were analysed as the study was terminated prematurely | Posted | Jun 2010 | Mean | 95% Confidence Interval | unit on scale | four monthly |
|
|
| 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. | Zero participants were analysed as the study was terminated prematurely | Posted | Jun 2010 | Number | 95% Confidence Interval | Participants | Baseline and weeks 2,4,6,8,12 and 16 |
|
|
| 0 |
| 15 |
| 15 |
| 15 |
| EG001 | 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 . | 1 | 19 | 18 | 19 |
| EG002 | 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 . | 0 | 16 | 15 | 16 |
| EG003 | 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. | 0 | 17 | 16 | 17 |
|
| Nasopharyngitis | Respiratory, thoracic and mediastinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Headache | General disorders | MedDRA (10.1) | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (10.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (10.1) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (10.1) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.1) | Systematic Assessment |
|
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| D012216 |
| Rheumatic Diseases |