Siemandi Clinical Trial 1997

A Randomized Clinical Trial

by Dr. H. Siemandi, M.D., PhD. et al

Objective

Recent published reports offer anecdotal evidence that cis-9-cetyl myristoleate may provide significant amelioration of various arthritic conditions. We set out to perform controlled studies to determine if this material was efficacious, either in the short term, or in some measurable manner, over a much longer period.

Methods

A prospective, randomized study design was used to allocate patients to receive sic-9-cetyl myristoleate, cis-9-cetyl myristoleate plus glucosamine hydrochloride (GH) sea cucumber(SC) and hydrolyzed cartilage (HC) and a placebo.

Results

At the start of this study, the duration, severity, and pattern of arthritic episodes were found to be similar in the 3 treatment groups. At the end of the study it was found that the number of arthritis episodes was significantly reduced and the duration of episode-free time was significantly prolonged, in the two cis-9-cetyl myristoleate groups compared with the placebo group.

Conclusion

Cis-9-cetyl myristoleate treatment and cis-9-cetyl myristoleate plus GH, SC, & HC were demonstrated to offer significant benefits over the placebo in the prevention of arthritis episodes. It was further determined that these results could not be obtained with other standard arthritic therapies based upon exhaustive reviews of patient records prior to opening of the study. Cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GH, SC & HC treatment also seems to permit some relief to autoimmune inflammatory diseases which may prove to be long-term. This finding could provide additional evidence for the theory, reflected by the earlier anecdotal evidence as well as some animal studies, that cis-9-cetyl myristoleate and cis-9-cetyl myristoleate plus GS, SC & HC may prove to be of major benefit in the future treatment of autoimmune diseases.

Patients & Methods

Study Design

The study was a 32 week (8 week cycle, 4 in hospital & 4 follow up) multicentric, double-blind, randomized, placebo controlled parallel trial that compared the efficacy of cis-9-cetyl myristoleate alone, and cis-9-cetyl myristoleate plus GS, SC & HC administered over a period of 30 days, with placebo, for the treatment of various forms of autoimmune diseases commonly characterized as arthritis and psoriasis. Out of a dose of 90 grams of total fatty acid estersa, 18 grams constituted cis-9-cetyl myristoleate. Those study patients who received the support nutrients GS, SC & HC were given a total dosage of 18 grams each of these nutrients. The study was conducted under the auspices of the Joint European Hospital Studies Program. This study was designed by a committee, which consisted of rheumatologists and biostatisticians experienced in the development and execution of clinical trials. Oversight of the study was accomplished by an executive committee, composed of the primary researcher and primary statistician, selected participating investigators, consultants, and an independent oversight committee consisting of two experienced federally controlled, state Health Department rheumatologists and one state Health Department biostatistician.

Eligibility Criteria

Patients were required to have inflammatory arthritis of at least one year duration in at least one peripheral joint, excluding the shoulders and hips. Included in this parameter, affected joints must have had joint tenderness and joint swelling of ≥ 2 on a four point scale and joint patient-physician overall assessment of involvement ranging from none-mild-moderate-severe-very severe. The patients inducted into this trial for the purposes of psoriatic testing were chosen on generally the same criteria-involvement of epidermal involvement from: none-mild-moderate-severe-very severe.

Criteria for exclusion included unwillingness to stop the use of tobacco and caffeinated beverages, at least for the duratino of the trial. Tobacco and caffeine use have been reported to greatly hamper the positive (if anecdotal) result of the use of cis-9-cetyl myristoleate. Is also should be noted here that the use of any other medication in all forms of arthritis as well as psoriasis were not excluded as it was determined this would limit participation. It was also deemed advisable to approximate as much as possible, conditions that would be found in the average arthritic. One exception to this condition was the exclusion of patients showing sensitivity to salicylates of ibuprofen which were used as excipeints in the placebo. Potential participants with other severe chronic conditions were excluded, as it was the opinion of the primary investigator that this type of participant would limit the potential successful completion of the study period.

All patients had failed to respond to therapy with therapeutic doses of one of the NSAIDs. All patients who took NSAIDs during the trial were required to be on stable dosages for one month prior to entry and throughout the trial. No systemic or intrarticular steroids were allowed.

Informed Consent

The study protocol was reviewed and approved by the federally controlled state oversight committee. Prior to entry into this trial, each potential study participant was informed of the nature, duration and purpose of the study to be administered and all the potential benefits, inconveniences, and hazards that could reasonably be expected.

Study Medication

Patients received either one-half liter of pleasantly flavored oral liquid containing 18 grams of cis-9-cetyl myristoleate or one half liter of the same liquid sans cis-9-cetyl myristoleate. Both liquids were carefully compounded so as not to be able to be differentiated. Each patient was also given 180 capsules of the adjunctive medication containing a total each of 18 grams GL, SC and HC. Identical capsules containing the placebo compound were also distributed. The cis-9-cetyl myristoleate topical liquid was distributed as a 25% concentration in 60cc. lightly scented lotion and in identical placebo lotion sans cis-9-cetyl myristoleate.The oral liquid was used with meals in one teaspoon quantities, three times daily. The topical lotion was used as needed and determined by each patient according to his or her own perceived requirement.

Clinical assessment

Outcome measures of disease activity and therapeutic efficacy were obtained at the time of screening (not more than four weeks before study entry) randomization at week zero, and thereafter at weeks 1,2,3 and 4. Outcome measures included a variety of patient reported, clinical, laboratory and radiographic assessments. Patient self-assessment measures included joint counts, dactylitis, Enthesopathy Index. Spondylitis articulare index, chest expansion, modified Schober’s test, finger to floor test and physician overall assessment as detailed elsewhere in this paper. Additionally, the presence of symptomatic keratoderma, phalangeal and digital deformation as measured from a normal range of vertical protrusion at rest were measured. These tests, singularly and collectively were then compiled into a patient by patient qualitative scale as none=0, mild=1, moderate=2, severr=3 and very severe= 4.

Laboratory Assessment

Laboratory evaluation included a urinalysis and complete blood cell count, with leujocyte differential and and reticulocyte count. Chemical surveys and Westerfren erythrocyte sedimentation rate (ESR) determination were done at every visit by secondary researchers daily in the two hospital settings. The C-reactive protein (CRP) level was evaluated at the first and last day of the hospital stay. At the screening times, blood was drawn for HLA-B27 typing and RF and ANA determinations.

Radiology Assessment

At the screening visit, all patients had the following radiographs performed: anteroposterior views of the pelvis and oblique views of the sacroiliac joints. Adverse drug reactions (ADR’s). Patients were screened for ADR’s at every secondary researcher’s visit. Patients were withdrawn from the study medication if any of the following were found: WBC less than 3000/mm, absolute polymorphonuclear count less than 100000/mm, acute or progressive decrease in hemoglobin or hermatocrit, proteinuria less than 500Mg for 24 hours, drug fever or significant rash.

Compliance

The patients were queried at each secondary researcher’s visit regarding the dietary supplement or topical lotion they had used. A capsule count of the trial medication was done at each consultation to monitor compliance.

Biostatistical Considerations

Each patient was classified as a treatment responder or non responder based on the following definition. Assessment measures were selected a priori, and criteria for clinical improvement and worsening were defined for each patient self-assessment and physician assessment (improvement category); joint pain/tenderness score and joint swelling score (improvement = decrease by 30%; worsening = increase by 30%). Treatment response was then defined as improvement in at least 2 of these 4 measures, one of which must be joint pain/tenderness or swelling, and ITO worsening any of the 4 measures. The study was designated with a 90% power for detecting a placebo response rate of 30% compared with a Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC response rate of 50%, assuming a 10% withdrawal rate. This resulted in a target sample size of 431 patients with an actual sample size of 382.

In short, the analytical method was the change in primary and secondary outcome measures from baselines to the last available follow-ups analyzed using t-tests for continuous data and chi-square tests for ordinal and categorical data. Mixed-model analyses were done to characterize the response patterns over time using SAS PROC MIXED for continuous data and a program named MIXOR for categorical and ordinal data. All other analyses were conducted using SAS version 6.08. All statistical tests were two-sided and P0.05 was the criterion for statistical significance.

Results

Patient population

Four hundred thirty-one patients entered the study. Of these, 106 were randomized to receive Cetyl Myristoleate, 84 were randomized to receive Cetyl Myristoleate plus GS, SC & HC; 226 received a placebo. Fifteen psoriatics received Cetyl Myristoleate plus GS, SC & HC, plus CM-25% concentration topical at a 3X quantity ratio. Even though the study was sponsored by the owners of the respective private hospitals, recruitment was not limited to the typical fee-paying patients. Approximately 27% of the patients were actively recruited in the respective local area. Despite a prolonged accrual period and careful screening, the loss of approximately 11% of the starting participants occurred largely because of the inability to stop the use of tobacco and/or caffeinated beverages.

Fulfillment of final parameter of study size was accomplished by the substantial excess of volunteers wanting to enter the study – this coupled with the relatively short testing period required to validate the effects of Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC.
Statistical Chart 1 outlines the baseline demographic, clinical, and laboratory variables. The duration of disease was 12 years. The Westergren ESR and CRP levels were mildly elevated. There were no statistically significant differences in any of these baseline parameters between the patients taking Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC and those taking placebo.

Compliance

Compliance for both the Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC and placebo groups was quite high. There was a statistical trend toward those in the Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC group taking more tablets per day (96% compliance) than those in the placebo group (86% compliance) (P = 0.08). The probability of this observation was due to the rapid response of pain relief in the Cetyl Myristoleate groups.

Primary outcome measures

The Oversight Committee defined response based on a decision rule as outlined in Patients and Methods. Statistical Chart 1 shows that based on that definition of treatment response, using the last-visit analysis, response rates were 63.3% in the Cetyl Myristoleate group and 87.3% in the Cetyl Myristoleate plus GS, SC & HC group and 14.5% in the placebo group. Trends favoring Cetyl Myristoleate and Cetyl Myristoleate plus GS, SC & HC groups were noted in components of the response definition. Physician overall assessment showed an improvement of 58.1% for the patients using Cetyl Myristoleate alone and 84.2% for the patients using Cetyl Myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 13.9% in placebo gradient overall assessment demonstrated 59.2% improvement in the Cetyl Myristoleate alone group and 88.2% in the Cetyl Myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 16.1% in placebo group. Joint swelling scores improved in 47.2% in patients using Cetyl Myristoleate alone and 77.2% in patients using Cetyl Myristoleate plus GS, SC & HC. Patients experiencing worsening or no reaction totaled 1.0% in all groups, compared with improvement of 21.1% in placebo group.

Secondary & laboratory outcome measures

Analysis of secondary outcome results (Statistical Chart 2) demonstrated a significant reduction in the Spondylitis Articular Index in the Cetyl Myristoleate group and in the Cetyl Myristoleate plus GS, SC & HC-treated patients. Trends favoring the Cetyl Myristoleate group and in the Cetyl Myristoleate plus GS, SC & HC group were also seen in a reduced duration of early stiffness and in an improvement in the fingers-to-floor result. Laboratory outcome measures showed some statistically significant changes. Total neutrophils decreased in the Cetyl Myristoleate group and in the Cetyl Myristoleate plus GS, SC & HC group compared with the placebo group. The Westergren ESR significantly decreased in the Cetyl Myristoleate group and in the Cetyl Myristoleate plus GS, SC & HC groups compared with the placebo group. The CRP values were not significantly different and the values in ESR for the responders was not statistically significant from the nonresponders.

Withdrawals and adverse drug reactions

Statistical Chart 3 summarizes the data of patient exits from the study. Forty-nine patients withdrew from the study before completing the study, 16 from the Cetyl Myristoleate and 10 from Cetyl Myristoleate plus GS, SC & HC groups, 2 from the psoriatic group, and 21 from the placebo group. Follow-ups in all groups averaged approximately these measurements were combined, combined average – (mean ± SD 6.97 ± .2.64 months) (P=.06). Withdrawal of consent was the most common reason for discontinuing the study. Seven patients withdrew because of no improvement or worsening disease. Two patients had to be withdrawn from the study because of concurrent illnesses requiring conflicting medication. The majority of withdrawals, however, was the result of patient addictions to nicotine, caffeine and alcohol and the patient inability to cease these activities during the study period.

Statistical chart 2 displays the percentages of study patients showing improvement in the primary outcome variables (columns 1-3). The numbers to the right display the significance levels for the differences between treatment groups (columns 4-6). All of the significant levels are much less than 0.05, which means the differences between groups are considered statistically valid. For all four primary outcome variables (treatment response, physician assessment, patient assessment and joint swelling score), Cetyl Myristoleate & GS, SC, and HC did significantly better than the Cetyl Myristoleate group, and the Cetyl Myristoleate group did significantly better than placebo. The chart also displays the results for the secondary outcome variables. The averages (mean average as opposed to median or mode) are presented in columns 1-3 along with their standard deviations (statistical measurement of data variations). Again, the numbers to the right display the significance levels for the difference between treatment groups (columns 4-6). “NS,” means that there was no significant difference between any measured groups labeled as such. When the groups are significantly different from each other, the significance is displayed. None of the secondary outcome variables were significantly different between the Cetyl Myristoleate group and placebo. The Cetyl Myristoleate & GS, SC, HC, group did significantly better than the placebo for dwelling score, Enthesopathy index, spondylitis articular index and the modified Schober’s test. The Cetyl Myristoleate & GS, SC, HC, group did better than Cetyl Myristoleate alone for the joint pain/tenderness score and the modified Schober’s test.

Discussion

The results of this trial suggest that Cetyl Myristoleate and Cetyl Myristoleate supporting formulas may be beneficial in the treatment of many forms of arthritic based diseases, including: psoriatic arthritis. The definition of response was determined a priori and included assessment of joint pain/tenderness and swelling as well as patient and physician overall assessments. Cetyl Myristoleate and supporting formulas produced the best treatment response by a factor of 72.8% more patients than did placebo. Considering the components of response individually Cetyl Myristoleate and supporting formulas resulted in 70.3% more patients having improved as assessed by physician, and 56.1% more having improved joint swelling. Therefore, while the amount of treatment response using Cetyl Myristoleate and Cetyl Myristoleate and supporting formulas seems to be consistent with the treatment affects on joint counts, it is obvious that there is a statistically significant improvement in the use of the CM with supporting formulas. The time-line based response rate of Cetyl Myristoleate and Cetyl Myristoleate supporting formulas, not adequately reflected in data, by patient, showed the majority of patients responding to Cetyl Myristoleate and Cetyl Myristoleate supporting formulas did so within the first three weeks. Also, not reflected in the data, was the continued use of Cetyl Myristoleate and Cetyl Myristoleate supporting formulas beyond the study time limits and dispensed on request to 21 patients. These 21 patients were determined to have received only marginal benefits from Cetyl Myristoleate and Cetyl Myristoleate supporting formulas but one more course of treatment showed responses approximately equal to the first patient response results.

Cetyl Myristoleate and Cetyl Myristoleate supporting formulas were well tolerated in this trial. This finding was not unexpected as Cetyl Myristoleate and the Cetyl Myristoleate supporting formula components are naturally occurring and have been used as diet supplementation for many years and are widely available singly and in various combinations. In summary, Cetyl Myristoleate and Cetyl Myristoleate supporting formulas appear to be beneficial in the treatment of a wide range of arthritic conditions including long standing and refractive cases.

SAN DIEGO CLINIC IMMUNOLOGICAL CENTER CLINICAL STUDY

San Diego Clinic Immunological

Center Clinical Study On

Cetylmyristoleate (CM8™) vs

Arthritis

A Study on Dose Effectiveness and Patient Response Conducted by the San Diego Immunological Center

The Purpose:

Having previously established the effectiveness and non toxicity of CM8 (cerasomal-cis-9-cetylmyristoleate) for arthritis symptoms of pain, inflammation, and impaired mobility, the purpose of the study was:

A) To determine optimum dosage levels for various types of arthritis,

B) To determine if different dosage levels would be required relative to the severity of each type of arthritis,

C) To observe response time required for initial and partial relief of symptoms,

D) To observe response time required for complete relief of symptoms, and

E) To determine factors influencing subjects who may not respond to the protocol.

The Subjects

Subjects were volunteers treated as outpatients. They presented with osteoarthritis, rheumatoid arthritis and other forms of reactive arthritis.

The Study

The study involved 48 subjects. Female subjects (28) ranged from 33 to 83 years of age. Male subjects (20) ranged from 29 to 74 years of age. All races and many ethnic backgrounds were represented. Age, gender, race, and ethnological background appeared to be irrelevant to patient response in this study.

The Protocol

CMO(tm) was administered orally in the form of 75mg capsules each morning and evening. The number of capsules and duration of treatment varied for each group of subjects. Subjects were advised to take capsules on an empty stomach with water only; and to avoid tea, chocolate, alcohol, coffee, cola, and other caffeinated drinks for five hours after taking the capsules.
Subjects were advised to completely avoid chocolate and alcohol during the entire trial period of two to three weeks duration. With a few exceptions for subjects who could not function without them, steroids were also prohibited. Otherwise diet was not controlled in any way. Subjects were permitted to continue taking their customary pain and nonsteroidal anti-inflammatory medications until they were no longer needed. Subjects were asked to visit or call in to report progress at least twice weekly.

The Results

Only two subjects failed to show marked or complete relief of all symptoms of pain and limited mobility normally associated with arthritis. Both of these nonresponding subjects had suffered prior hepatic problems: one from alcohol abuse resulting in cirrhoses of the liver; the other, a former professional athlete, presented with considerable liver damage from steroid abuse. Further studies are necessary to determine the role of liver function capacity with respect to this protocol. Liver damage resulting from steroids previously prescribed for arthritis may also prove to be a factor affecting patient response.

Group #1

Mild to moderately severe osteoarthritis & and reactive psoriatic arthritis.

In Group #1, eleven (11) subjects presented with mild to moderately severe osteoarthritis and one with reactive psoriatic arthritis were supplied with 16 capsules, two 75mg capsules to be taken each morning and evening for four days.

Nine reported about 20% to 30% improvement in articulation and inflammation and about 40% to 50% relief of arthritic pain within 36 hours. In these nine subjects, improvement continued rapidly for the next 60 hours, reaching a 70% to 80% improvement by the end of the four days. Two of the subjects continued to improve over the  following week despite the fact they were no longer taking any capsules. However about half of this group experienced the return of some mild arthritic symptoms after about three to five weeks. (Although not included as part of this study, all the subjects in this group were treated again and their symptoms have not returned.) The patient with reactive psoriatic arthritis also experienced an almost complete reversal of his associated very severe psoriatic skin condition affecting about 20% of his total skin area.

Group #2

Severe to crippling rheumatoid arthritis In Group #2, nine (9) subjects presenting with severe to crippling rheumatoid arthritis were supplied with 50 capsules to be taken in two series, two 75mg capsules each morning and evening for seven days, with a seven day interval before repeating the same dosage for 5 1/2 more days. Four of these subjects were unable to walk and were accustomed to being transported by wheelchairs. One, her femur being fused at the hip, was unable to achieve a sitting position for wheelchair transport. She could, however, move about slowly on crutches as long as she was accompanied by someone to aid her in maintaining her balance.  Otherwise she could only stand or lie down. The remaining four could move about with canes or walkers. All nine subjects presented with pain, inflammation, and marked deformation of nearly all proximal interphalangeal and large joints. Five presented with limited lumbar flexion and pain in the vertebral column. All had difficulty grasping and manipulating common objects. On the fourteenth day, at the end of the one week interval without treatment, six(6) subjects reported minor continuing improvement; two reported maintaining their improved status and one continued to show no improvement. Treatment was resume an the fifteenth day for 5 1/2 more days. By the end of the treatment period, all but two subjects reported to be 90% free of pain with a return of 70% to 100% mobility. The fused hip joint remained fused, of course, but with a return of over 70% mobility in other joints, the subject felt hip surgery now to be worth consideration. The nonresponsive subject proved to have cirrhosis of the liver, which may have been the reason for her inability to respond to treatment. Further investigation is necessary to determine the role of liver function in this protocol.

Group #3

Mild to moderately severe rheumatoid arthritis

In Group #3, fourteen (14) subjects presenting with mild to moderately severe rheumatoid arthritis were supplied with 24 capsules, two 75mg capsules to be taken each morning and evening for 6 days. After three days of treatment, eleven reported about 20% to 30% improvement in articulation and inflammation, and about 40% to 50% relief of arthritic pain. In these eleven subjects, improvement continued rapidly over the next four days, approaching the 80% to 100% level. The remaining three subjects reported similar improvement by the end of the fourth day, with an overall improvement of 70% to 80% after seven days.

Most of the subjects continued to report minor additional improvement for one week or more, even though they were no longer under treatment. However, six in this group began to experience the return of some mild arthritic symptoms after about three to four weeks. (Although not included as part of this study, all subjects in this group were treated again and their level of improvement has subsequently stabilized.)

Group #4

Severe to crippling osteoarthritis

In Group #4, fourteen (14) subjects presenting with severe to crippling osteoarthritis were supplied with 50 capsules to be taken in two series, two 75mg capsules each morning and evening for seven days, with a seven day interval before repeating the same dosage for 5 1/2 more days. Three of these subject were unable to walk and were accustomed to being transported by wheelchairs. The other eleven could move with crutches, walkers and canes. All presented with pain, inflammation and marked deformation of nearly all interphalangeal and large joints. Four presented with limited lumbar flexion and pain in the vertebral column. Ten had difficulty grasping and manipulating common objects.

After four days of treatment, ten in this group reported 30% to 50% improvement in articulation and inflammation and about 40% to 60% relief of arthritic pain. In these ten subjects, improvement continued rapidly over the next three days, reaching 80% to 100% by the end of seven days. One reported no perceptible change.
On the fourteenth day, at the end of the one week interval with out treatment, nine subject reported continuing minor improvement, four reported maintaining their improved status and one continued to show no improvement. Treatment was resumed on the fifteenth day for 5 1/2 more days.

By the end of the treatment period, eleven subjects reported 80% to 100% relief of pain with a return of 80% to 100% mobility. Two subjects reported a 70% to 80% of articular mobility with a 70% to 90% reduction of arthritic pain. The one non-responsive subject proven to have previous liver damage as a result of sports related steroid abuse. Further studies are necessary to determine the role of liver function in this protocol.

Summary

The results of this study lead to several conclusions regarding its five principal objectives:

1) Optimum dosage levels appears to be equal for all three types of arthritis investigated: osteoarthritis, rheumatoid arthritis and reactive psoriatic arthritis. This is evidenced by the gradual return of minor arthritis symptoms in several of those treated with only 16 to 24 capsules, and no regression in those treated with 50 capsules in two series separated by one week without treatment.

2) Dosage level requirements appear to be equal irrespective of the severity of the subjects condition.

3) Initial response time for minor improvement appears to vary from two to seven days, irrespective of the severity of the subject’s condition.

4) The time for maximum attainable response appears to vary from seven to twenty one days, resulting in 70% to 100% overall improvement. (Apart from this study, three of the most severely afflicted subjects were treated again after a five week interval, resulting in an additional 10% to 20% overall improvement.)

5) The two non-responding subjects both proved to have suffered previous damage to the liver from steroid or alcohol abuse, indicating that impaired liver function may preclude success with this protocol.

In addition, it was evident that for many subjects, the relief of inflammation resulted in marked improvement in joint deformation.