2009-04-06: After more than a decade of outrages Dr. Kaplan's much-ballyhooed RCT testing MCN36
[aka EmpowerPlus] in adult subjects with bipolar disorder was terminated on 2009-03-10, having enrolled an embarrassing 34 of the projected 96 subjects since opening in 2005. According to the trial registration, investigators were unable to recruit enough subjects, the trial was plagued by large expectancy effects,
and the results were uninformative with respect to efficacy. Bizarrely enough the investigators assert no adverse events were recorded. If this were true it would be a bona fide miracle because adverse events occur in every trial. Perhaps the large expectancy effects had something to do with Dr. Kaplan's proclamation to the media that she'd totally cured bipolar disorder.
Do you think?
Clinical Trial of a Nutritional Supplement in Adults With Bipolar Disorder (NCT00109577). Clinicaltrials.gov. Accessed on 2009-04-06 at: http://www.clinicaltrials.gov/ct2/show/NCT00109577
(Clinical trials are presented in approximate ascending chronological order.)
The sources of the information about the clinicals below are a combination of ATI/FOIA disclosures from the University of Calgary and publicly available information in University of Calgary databases: Summary Reports of Regional Research Activity Approved Studies (Pre-2002 to Present) and Studies Closed to Research (Pre-2002 to Present). Accessed on 2009-04-06 at: http://web.archive.org/web/20070327033051/www.ucalgary.ca/md/CAH/research/forms/index.html
So what's to notice here? First the relatively obvious: more than a dozen clinical trials were conducted or approved in the absence of basic manufacturing, toxicity, or safety information, without animal studies, or a plausible hypothesis as to how or why the investigational drug[s] might be safe or effective to treat bipolar disorder, anxiety or mood disorders, ADHD, autism, schizophrenia, or fibromyalgia. This flies in the face of ethical principles — humans are test subjects of the last resort, not the first, and surely children should not be exposed to an investigational drug before it's tested in adults.
Other troublesome issues on a long list are: several studies were never published, leading us to wonder why; 2 clinical trials conducted on children have no record of REB approval that we can discover, suggesting they might have been conducted without it; and one study title does not match its publication title with respect to diagnosis, suggesting the possibility of retroactive protocol revision or selective reporting of results.
Consent Forms: Perhaps most distressing of all is the lack of accurate information provided to research subjects or legal representatives in the consent forms. No information was provided about the safety or efficacy of high doses of vitamins and minerals in EmpowerPlus for the treatment or amelioration of bipolar disorder (or fibromyalgia or pervasive developmental disorder); no information was provided about the risk of severe adverse reactions between commonly prescribed medicines many research subjects were taking and EmpowerPlus, although these were well known to Dr. Kaplan and the distributor of EmpowerPlus; there was no disclosure that the randomized placebo controlled trial in subjects diagnosed with bipolar disorder required a medication wash-out period prior to entry, nor that subjects would be prohibited from taking medications during the 6-month trial. If fact, the consent form for the randomized placebo controlled trial in subjects diagnosed with bipolar disorder explicitly misled subjects by describing how their personal psychiatrists would be able to adjust medications during the course of the study.
Each of the consent forms provided identical information to subjects about the safety of EmpowerPlus, the investigational drug they would be given: 12 children in a previous study had experienced no adverse events. As it turns out, 7 of the 12 children dropped out and none of the 12 children were given EmpowerPlus. In the adult open label study in subjects with bipolar disorder, pregnant women and women of child-bearing age were not excluded or warned to use contraceptives because of the risk to a fetus from the large amounts of vitamin A in EmpowerPlus. Oddly enough, in the consent form for the randomized controlled trial in subjects with bipolar disorder, there was such a warning and exclusion criteria.
These failures are right out of the pages of the dark age of psychiatric research.
Sources:
Clinical Trial 1
Kaplan Initial 1: B GRANT-ID: 9621
TITLE: A Double Blind Case Controlled Study of the Effects of a Vitamin Mineral Supplement as an Adjunctive Therapy for Attention Deficit Hyperactivity Disorder (ADHD)
Approval: 3 April 1997
Source-ID_Source: Nil Source-ID_3_Source:
Source-ID_2_Source: Source-ID_4_Source:
Category: Completed Decision Date: September 26, 2000
NOTES: A total of 12 patients were recruited with 7 withdrawals. Study completed in June 1998.
Source: University of Calgary Cumulative Summary of Closed Protocols. 2002-09-12. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_pre02.html
According to Professor Brian Kolb Ph.D., a co-investigator from the University of Lethbridge, the results of this trial were equivocal
and marked the end of his involvement with the research, though an earlier trial he had conducted on a handful of children suggested some possibility of benefit. The results are unpublished. The informed consent for the subsequent pediatric study titled Open Trials of Nutritional Supplements for the Treatment of Children with Anxiety/Mood Problems
claimed that children in an earlier study
[this one] suffered no adverse events, ostensibly to reassure the subjects' parents.
This is unfortunate because the two studies did not test the same drug: the 1997 study (above) used a combination of investigational products from Melaleuca Inc., Body Systems Technologies, and T.J. Clark Inc., with some 96 or so different ingredients, while the subsequent study (Clinical Trial 5, below) used EmpowerPlus, which contained 36 ingredients.
Sources: Munn Gafuik J-A. University of Calgary Response to Access Request 01-015. Disclosure Request No. 6, identity of manufacturer of investigation nutritional supplement in studies (d) and (e) [p. 3], and List of Disclosures No. 6, for study (e) Melaleuca Inc., Body Systems, T.J. Clark [p. 3 of 4]. 2002-02-25. Available from http://www.circare.org/FOIA/ucati_01-015.pdf. Compare this with: Kaplan BJ, Simpson JSA, Ferre R, Gorman CP, McMullen D. Successful Treatment of Bipolar Disorder with a Nutritional Supplement: Ten Cases. Poster presented at the Canadian Psychiatric Association annual meeting in Victoria, B.C. 2000-10-04, list of ingredients in EmpowerPlus, Table 2, p. 9. Available from http://www.circare.org/FOIA/cpa_2000_FINAL_poster.pdf
It's difficult to see how the conflation of two different investigational products meets either the spirit or the standards for informed consent. Furthermore, one wonders what accounts for the relatively large number of drop-outs, which exceeded 50% of the subjects enrolled in the trial. Finally, in response to our ATI request for information about this study, Calgary wrote that 12 children completed the trial, contradicting the information in their research database, of 7 drop-outs and 5 completers. Oddly enough, Calgary refused to release the consent form for this study on the grounds that it was the property of the researcher.
This is not only odd, it's very nearly perverse: Calgary did provide four other informed consents, which were also the property of the researcher
and we suppose that the subjects' parents or guardians also have this property of the researcher
as well.
Clinical Trial 2
We know little more about this study than the fact it was published. There is no entry in the Calgary approvals or closures database to suggest REB approval, and since we became of aware of it many months after our FOIA/ATI requests to the University of Calgary, a third request would have been necessary and was beyond our financial resources.
Source: University of Calgary Cumulative Summary of Closed Protocols / No Entry. 2002-09-12. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_pre02.html
The article does, however, describe 2 children, 8 and 12 years of age, who were given the full adult dosage of EmpowerPlus of 32 capsules a day and maintained on this dose for many months. According to the label, this meant they were exposed to levels of at least 9 vitamins and minerals, including vitamin A, in excess of the Tolerable Upper Limits (daily) for adults. Independent laboratory testing commissioned by the Schizophrenia Society of Ontario suggests this exposure might have been even more excessive.
Source: Health Canada ATI A 2002-00199/ms. ATIP2283, ATIP2285, ATIP2286, ATIP2287, ATIP2288, ATIP2289: L. Wall and M. Alberti, Schizophrenia Society of Ontario. Letter to the Honorable Ann McLellan, Minister of Health, re: EmpowerPlus; expression of concern for safety of constituents; summary of independent laboratory analysis. 2002-03-08. Available from http://www.circare.org/FOIA/hcati2_283289.pdf
The children were exposed to high doses of vitamins and minerals in the absence of any suggestion that they were refractory to available treatments; in the absence of any indication of diagnosed deficiencies; in the absence of a credible causal relationship between vitamin or mineral deficiencies and pervasive developmental disorder, and in the absence of any indication that addressing vitamin or mineral deficiencies, even if they existed, would treat or ameliorate the symptoms of pervasive developmental disorder. This seems reckless. Because none of the informed consents we obtained discuss the high dosages of vitamins and minerals in the investigational drug, we have no reason to believe the consent for this study was any different. This suggests these children were exposed to risks that were not adequately disclosed to their parents. Informed consent cannot be obtained where disclosure is inadequate.
Publication: Kaplan BJ, Crawford SG, Gardner B, Farrelly G. Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children. J Child Adolesc Psychopharmacol. 2002;12(3):205-19. Mary Ann Liebert, Inc. abstract available from http://www.liebertonline.com/doi/abs/10.1089/104454602760386897
A reprint of this article is available on the web site of The International Child Development Resource Center at http://www.icdrc.org/pdf/mood%20and%20minerals%20vitamins.pdf
Clinical Trial 3
Kaplan Initial 1: B GRANT-ID: 10326
TITLE: Open Trials of Nutrient Supplements
Source-ID_Source: Nil Source-ID_3_Source:
Source-ID_2_Source: Source-ID_4_Source:
Category: Completed Decision Date: March 11, 2002
NOTES: 24 subjects accrued; 2 subjects withdrew.
Source: University of Calgary Cumulative Summary of Closed Protocols / 2002. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_02.html
We don't have an approval date for this trial, but grant ID 10326 suggests the approval was prior to grant ID 10561, the open label trial (Clinical Trial No. 4, below) for which we have a Conjoint Health Research Ethics Board approval date. This study is nowhere described in detail, but perhaps it was this trial to which co-investigator Chris Gorman MD referred in a blurb he wrote for the newsletter of the Mood Disorder Society of British Columbia. According to him, an earlier trial had been conducted in subjects with various
psychiatric disorders with equivocal results. Since when has it become acceptable to enroll subjects with various disorders — apparently willy-nilly — instead of limiting enrollment to those subjects most likely to respond to the test article? Common sense also suggests researchers are motivated to publish favorable results in preference to negative ones.
Clinical Trial 4
Kaplan Initial 1: B GRANT-ID: 10561
TITLE: Open Trials of a Nutraceutical Treatment for Mental Disorders in Adults
CHREB Approval: May 6, 1999
Source-ID_Source: Nil Source-ID_3_Source:
Source-ID_2_Source: Source-ID_4_Source:
Category: Discontinued Decision Date: September 9, 2002
NOTES: A total of 26 subjects were recruited with 12 withdrawals. Terminated due to Health Canada decree.
Source: University of Calgary Cumulative Summary of Closed Protocols / 2002. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_02.html
The statement in the NOTES (above) that this trial was terminated due to Health Canada decree
may be inaccurate. Health Canada directed Dr. Kaplan via letter to Ian Mitchell, chair of the Conjoint Health Research Ethics Board, to terminate the randomized placebo controlled trial in adults with bipolar disorder. There was no mention of this open label study in the Health Canada correspondence to Dr. Kaplan or Dr. Mitchell.
Source: Akoury M. Health Canada letter to Ian Mitchell with attached document, Information Request to Bonnie J. Kaplan Ph.D., re: studies titled Nutraceutical Treatment of Mental Disorders in Adults: An RCT with Bipolar Disorder
and Fibromyalgia Clinical Study.
(2001-10-25) 2002-01-04. Available from http://www.circare.org/FOIA/hc_cta_20020104.pdf
Consent Form for this trial: University of Calgary Access Request 01-010 Disclosure. Kaplan BJ. Consent Form. Open Trials of a Nutraceutical Treatment for Mental Disorders in Adults. 2001-11-07. Available from http://www.circare.org/FOIA/uc_133_134.pdf
This trial included American subjects at the University of Utah, who were enrolled by Dr Ferre despite the fact that the Utah IRB refused to approve it — as described in the OHRP determination letter of 2002-08-02, and in direct contradiction of Dr Kaplan's claim of ethical approval in the Journal of Clinical Psychiatry. It's bad enough that our system of human research protection regularly fails to protect research participants, now it seems we need to worry about foreign nations or their agents who see fit to conduct research on Americans in defiance of American IRB decisions, and do so despite having an approved Federal Wide Assurance on file with OHRP, and in which they pledge to uphold the very guidelines violated in this clinical trial.
Read the the determination letter from the U.S. Office for Human Research Protections (OHRP):
McNeilly PJ. Office for Human Research Protections Determination Letter to the University of Utah re: Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. Journal of Clinical Psychiatry. 2001;62(12):936-944. 2002-08-19. Available from http://www.hhs.gov/ohrp/detrm_letrs/YR02/aug02e.pdf
OHRP determined that research with E M Power+ was conducted despite the fact that University of Utah Institutional Review Board refused to approve proposed research testing EmpowerPlus on a number of previous occasions. OHRP and the University of Utah both agreed informed consent was inadequate.
CIRCARE wrote this InfoMail before OHRP issued its determination letter:
Concerns Regarding a Nutritional Cure. CIRCARE InfoMail, 2002-06-27. Available from http://www.circare.org/im/im27June2002.htm
This trial is the adult open-label study of 11 subjects which featured so prominently in the media hoopla, and is presumably the basis for Dr. Kaplan's extremely questionable claim to have totally cured bipolar disorder.
Source: ATIP1299, ATIP1300, ATIP1301, ATIP1302: Health Canada internal documents / Ottawa Citizen news story reprint: Mineral pills for pigs 'totally cure' bipolar disorder. Joanne Laucius. The Ottawa Citizen. 2001-07-04. Available from http://www.circare.org/FOIA/hcati1_299302.pdf
The file linked below (presentations) is the original poster presented at the meeting of the Canadian Psychiatric Association, and later published in the Journal of Clinical Psychiatry in December, 2001. A complete list of ingredients for the investigational drug product EmpowerPlus is on page 9 — 36 vitamins, minerals, herbs and amino acids, and a fair number in relatively shocking amounts. Not did only EmpowerPlus require an approved Clinical Trials License and Investigational New Drug Application (as per the Health Canada ATI disclosures), several individual ingredients would have required approved Investigational New Drug Applications prior to use in human clinical trials, yet none were applied for. And as you'll see on the following pages, this became a contentious issue and gave rise to some rather creative responses.
Straight away you should wonder what we're talking about with 11 subjects
when the database claims a total of 26 subjects were enrolled. The poster presentation of this trial in December 2000 reported on 10 subjects, and the published version, accepted upon revision by the Journal of Clinical Psychiatry in June 2001 reported on 11 subjects of a total of 14 initially enrolled in the trial. It's a rather unsettling coincidence that the difference between total enrollment and drop-outs reported in the Calgary database is 14, and this should be the very same number given in the publication as the total trial enrollment. This coincidence bears an uncomfortable similarity to the disagreement between the Calgary research database, their ATI disclosure, and subsequent representation in a later informed consent regarding total enrollment vs. completers and drop-outs in the ADHD study. This raises concern about selective reporting of data, or suppression of disconfirming data. This concern is intensified by the fact that the approved trial intended to collect data on subjects with mental disorders
yet the publication of same offers data on a sub-set of subjects with bipolar disorder. Publication of a narrower selection of subjects than originally planned increases suspicion of selective data reporting. Is it possible that an additional 14 subjects enrolled in this trial, 8 of whom dropped out, at some point after acceptance for publication in June 2001? Of course it's possible but after you finish reading the material we've compiled on this research and the way it was conducted, consider whether it's probable.
We'll spare readers the headache and point out some of the more glaring problems: Dr. Kaplan represents this study as an indication of the efficacy of EmpowerPlus, manufactured and provided by Evince International of Farmington, Utah. Fine. Evince International was initially incorporated in December 1999 — so how is it that over half the subjects are reported to be taking the investigational drug as much as 11 months before the company asserted to manufacture it existed? Start with the subject who is reported to have been on the supplement
for 68 weeks according to the poster – the poster presented in December 2000. The likeliest explanation is that the subjects were given more than one investigational product during the course of the trial, and also suggests the results may be confounded by the use of different investigational products. Put differently, if the experimental agent worked
which one of the two was responsible?
In fact, there is credible evidence that this is precisely what happened. Dr Kaplan wrote that EmpowerPlus first became available for use in April 2000 (see p. 1 of the poster presentation to the Canadian Psychiatric Association in 2000). Additionally, in an interview with a representative of the Schizophrenia Society of Ontario, research subject Steve Morton said the investigational drug changed in March or April of 2000 and he understood the researchers to explain the difference came from changing the binding agents or something.
If true, the data might be very unreliable. The research subjects have reason to be mad as hell that their altruistic intent was diverted and their health potentially put at risk for naught. And if this were not enough, you'll notice in the poster presentation two subjects are reported to have stopped taking the investigational drug and to have deteriorated
yet this is not reported in the journal publication.
Presentations of this trial: Kaplan BJ, Simpson JSA, Ferre RC, Gorman CP, McMullen DM. Successful Treatment of Bipolar Disorder with a Nutritional Supplement: Ten Cases. Poster presented at the Canadian Psychiatric Association annual meeting in Victoria, B.C. 2000-10-04. Available from http://www.circare.org/FOIA/cpa_2000_FINAL_poster.pdf
It seems like Dr. Kaplan was extremely pleased with this research, because she put the abstract on her department web site. Twice.
Publication of this trial: Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. Journal of Clinical Psychiatry. 2001;62(12):936-944. PubMed abstract available from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11780873
A reprint of this study, including comments by Charles Popper M.D., is available from http://tinyurl.com/kfzpj
Funding for this trial: Alberta Science and Research Authority [Project number: 99-03A], Alberta Children's Hospital Foundation, and Evince International, LLC.
Clinical Trial 5
Kaplan B, Ferre RC, Simpson JSA, Crawford SG, Fisher GC.
TITLE: Open trials of nutritional supplements for the treatment of children with anxiety/mood problems (as per title in consent form)
Funding: unknown
Status: still enrolling children as of Spring 2001.
Consent Form for this trial: University of Calgary Access Request 01-010 Disclosure. Kaplan BJ. Consent Form. Open Trials of Nutritional Supplements for the Treatment of Children with Anxiety/Mood Problems. 2001-11-07. Available from http://www.circare.org/FOIA/uc_135_136.pdf
There is no entry in the University of Calgary's research approvals or closures database to indicate this trial had requisite approvals from the Conjoint Health Research Ethics Board or the Child Health Research Committee. Yet in response to our ATI request, the University of Calgary asserted Conjoint Health Research Ethics Board approval was given on May 26, 1999. This disagreement is disturbing. It's always troubling to suppose research might be conducted on human subjects without prior IRB or REB review and approval, but it's more disturbing to think review and approval were absent for a phase I clinical trial conducted on children. Is this a simple omission, a clerical error if you will, or was the trial conducted without approval from the Conjoint Health Research Ethics Board? In our opinion, the inaccuracies in the informed consent suggest lack of Conjoint Health Research Ethics Board approval, or that approval was granted without adequate information.
Sources:
Consider: would the Conjoint Health Research Ethics Board knowingly approve an informed consent which represented purported safety data from drug X as safety data for drug Y? You hope not because it's overtly deceptive and misleading.
We also know for certain that the American children in Utah (Dr Ferre's subjects), were not only enrolled in a clinical trial without Institutional Review Board approval, these children were enrolled in a clinical trial the Utah Institutional Review Board explicitly refused to approve. Taken together, and given the absence of any indication of Conjoint Health Research Ethics Board review and approval for another study (Clinical Trial no. 2, above) at best, research oversight was erratic in these instances.
Presentations of this trial: In some cases the data appears to have been presented together with the results of the adult open label study (Clinical Trial no. 4, above); at 2 conferences this pediatric study was presented alone, while in the case of other presentations, we cannot be sure what study was presented.
According the distributor's web site (www.truehope.com), this trial or some combination of trials have also been presented at:
Publication: Kaplan BJ, Fisher JE, Crawford SG, Field CJ, Kolb B. Improved mood and behavior during treatment with a vitamin-mineral supplement: An open-label case series of children. J Child Adolesc Psychopharmacol. 2004;14(1):115-22. Mary Ann Liebert, Inc. abstract available from http://www.liebertonline.com/doi/abs/10.1089/104454604773840553?journalCode=cap
A notice of forthcoming publication appeared in the footnotes of Kaplan BJ, Crawford SG, Gardner B, Farrelly G. Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children. J Child Adolesc Psychopharmacol. 2002;12(3):205-19. We assumed the notice refers to this trial because it surely cannot refer to the ADHD trial completed in 1998, and no other entries in the Calgary database for Dr. Kaplan resemble the study-title in the notice. Unfortunately the notice raises yet another problem: Brian Kolb ended his involvement with this research at the conclusion of the equivocal
ADHD study in 1998. In response to a letter of inquiry from Terry Polevoy M.D. regarding this notice, Dr. Kolb explicitly denied ever having written a paper with Dr. Kaplan.
One problem with the study publication is quite striking indeed: the author-investigators have changed. In 2001, Kaplan BJ, Simpson JSA, Crawford SG, Ferre RC, Fisher GC presented data from this study at a meeting in London in 2001. Kaplan BJ, Simpson JSA, Ferre RC, and Crawford SG presented data from this study at a meeting in New Orleans in 2001. Fisher JE, Field CJ, Kolb B. are nowhere in evidence in previous presentations, or in the absurd media circus that surrounded this research at the time. Ferre RC and Fisher GC certainly were investigators in this study yet they are absent from the list of authors of the study publication. It might be objected that there were two separate studies, and so explains the different authors, except for one insurmountable difficulty: both the 2004 publication and the 2001 London presentation report virtually identical data on nine children. While there might be two separate studies that enrolled two different groups of nine children, the probability that two different studies enrolled two different groups of nine subjects and reported identical results is nil.
The results from the 2004 publication and the previous conference presentations are compared in this table.
| Title | J Child Adolesc Psychopharmacol. 2004;14(1):115-22. | European Congress of Psychology. London, UK. 2001-07-1. | Society of Biological Psychiatry. New Orleans, LA. 2001-05-04. |
|---|---|---|---|
| Sample Size | N=11 (7 M, 4 F; ages 8-15) 9 Completed | N=9 (6 M, 3 F ages 8-15) | N=9 (ages 8-15) |
| Study Period | >8 weeks | 8 weeks | 14 weeks |
| Psychometric Test 1 | CBCL: Withdrawn behavior – t(8)=3.79, p<.01 | CBCL, YOQ, YMRS | CBCL: withdrawn (t(8)=3.79, p<.01) |
| Psychometric Test 2 | Anxious/depressed – t(8)=2.97, p<.05 | CBCL, YOQ, YMRS | anxiety problems (t(8)=2.97, p<.05) |
| Psychometric Test 3 | Social problems – t(8)=2.89, p<.05 | CBCL, YOQ, YMRS | Social problems t(8)=2.89, p<.05 |
| Psychometric Test 4 | Thought problems – t(8)=3.67, p<.01 | CBCL, YOQ, YMRS | Thought problems t(8)=3.67, p<.01 |
| Psychometric Test 5 | Attention problems – t(8)=3.85, p<.01 | CBCL, YOQ, YMRS | Attention problems t(8)=3.85, p<.01 |
| Psychometric Test 6 | Delinquent behaviour – t(8)=3.71, p<.01 | CBCL, YOQ, YMRS | Delinquent behaviour t(8)=3.71, p<.01 |
| Psychometric Test 7 | Delinquent behaviour – t(8)=3.71, p<.01 | CBCL, YOQ, YMRS | Delinquent behaviour t(8)=3.71, p<.01 |
| Psychometric Test 8 | YOQ – t(8)=5.97, p<.001 | CBCL, YOQ, YMRS | YOQ: t(8)=5.97, p<.001 |
| Psychometric Test 9 | YMRS – t(3)=4.54, p<.05 | CBCL, YOQ, YMRS | YMRS: t(3)=4.54, p<.05 |
| Authors | BJ Kaplan, Jennifer Fisher, SG Crawford, CJ Field, B Kolb | BJ Kaplan, S Simpson, SG Crawford, RC Ferre, Geoff Fisher | BJ Kaplan, S Simpson, SG Crawford, RC Ferre, D McMullen, C Gorman |
Sources:
Readers are left to draw their own conclusions.
Clinical Trial 6
Kaplan Initial 1: B (JSA Simpson, C Gorman, W Friend, M Trew, R Dickson and others.)
GRANT-ID: 10671
TITLE: Nutraceutical Treatment of Mental Disorders: An RCT with Bipolar Disorder
CHREB approval: August 24, 1999
Source-ID_Source: AB Science & Research Source-ID_3_Source:
Source-ID_2_Source: Source-ID_4_Source:
Category: Discontinued
Decision Date: September 9, 2002
NOTES: A total of 28 subjects were recruited with 13 withdrawals.
Funding for this trial: Alberta Science and Research Authority (Project number: 99-03A, $588,757)
Consent Form for this trial: University of Calgary Access Request 01-010 Disclosure. Kaplan BJ. Consent Form. Nutraceutical Treatment of Mental Disorders in Adults: An RCT with Bipolar Disorder. 2001-11-07. Available from http://www.circare.org/FOIA/uc_137_139.pdf
Health Canada directed this trial be terminated on 2002-01-04 by letter to Dr Ian Mitchell, Director of the Office of Medical Bioethics at Calgary. Yet the closure entry gives no indication of this, and it should do, because the termination of research by the regulator is sufficiently rare and serious to be retained in permanent records. If the CHREB approval date is correct as offered by the University of Calgary, its REB approved human testing of an investigational drug against a placebo 8 months before the drug (EmpowerPlus) first existed. Such approvals do not inspire confidence. Nor does the fact that there is no indication of approval by the Children Health Research Committee, when Dr Kaplan enrolled, or planned to enroll, children in this trial.
Sources:
Nutraceutical Treatment of Mental Disorders in Adults: An RCT with Bipolar Disorderand
Fibromyalgia Clinical Study.(2001-10-25) 2002-01-04. Available from http://www.circare.org/FOIA/hc_cta_20020104.pdf
Clinical Trial 7
Kaplan, B & Tim Yates
TITLE: A randomized, controlled trial of chelated mineral supplement in unmedicated children with Pervasive Developmental Disorder
Awarded June 2001
Funding: Medical Services Foundation of Alberta
Status: pending Health Canada approval
Clinical Trial 8
Kaplan, B
Clinical trial: head-to-head comparison of EmpowerPlus and conventional pharmaceutical treatment in adolescents newly diagnosed with mood disorders
Awarded June 2001
Funding: Medical Services Foundation of Alberta
Status: pending Health Canada approval
Clinical Trial 9
Kaplan, B
Clinical trial: teens, adolescents, and adults with mood disorders not otherwise specified
Awarded June 2001
Funding: Medical Services Foundation of Alberta
Status: pending Health Canada approval
We learned about clinical trials numbers 7, 8, and 9 in early 2001 from media reports and from Brent Scott M.D., Chairman of the Department of Pediatrics, and apparently Dr. Kaplan's immediate superior. A follow-up call to the Medical Services Foundation of Alberta confirmed the awards and added that despite earlier reassurances to the contrary, Dr Kaplan's most recent communication indicated that Health Canada had refused to grant a Clinical Trials License for the studies. The Medical Services Foundation of Alberta should be commended for being requiring proof of compliance with the Canadian federal Food and Drugs Act prior to releasing funds for human research. What's the matter with all the other Alberta provincial funding agencies? And like the other trials with EmpowerPlus, the approval of these studies also suggest inadequate REB review. The issues should be familiar by now:
The Conjoint Health Research Ethics Board members seemed to have overlooked large chunks of Health Canada regulations governing the testing of investigational new drugs — regulations which Calgary pledged to uphold as a condition of funding awards from the Canadian Health Research Institute.
In her curriculum vitae (2005) Dr. Kaplan states she declined the $100,000 grant award by the Medical Services Foundation of Alberta. Curriculum Vitae of Bonnie J. Kaplan Ph.D. 2005. P.6. Available from http://www.danoneinstitute-can.com/pdf_files/cv/bonnie_kaplan.pdf
Clinical Trial 10
Kaplan, B.
Awarded: December 2001
Award to conduct a randomized clinical trial with placebo testing EmpowerPlus as monotherapy on 88 subjects diagnosed with bipolar disorder
Status: pending, for written determination from U.S. FDA re: Investigational New Drug Application and IRB approval
Interested readers should contact Dr Kaplan at the University of Calgary for details. It's worrying that Calgary would approve proposals such that Dr Kaplan was conducting 2 identical high-risk clinical trials simultaneously. Provided the first placebo controlled trial is well done, a second identical and concurrent trial adds nothing, but rather might expose twice as many research subjects to harm than is necessary to the answer the research question, or more precisely, to prove or disprove the null hypothesis.
Clinical Trial 11
Kaplan, B
GRANT-ID: 16641
Title: A Nutritional Supplement for the Treatment of Bipolar Disorder: a Pilot Placebo-Controlled Study of Safety and Efficacy.
CHREB Approval: 10/5/2002 ARC Approval: 7/29/2002 CHSRC Approval:
Source-ID_Source: Alberta Science and Research Source-ID_3_Source:
Category: Withdrawn Decision Date: November 15, 2004
NOTES: This study was never initiated.
Sources:
Not only is the title is a non-sequitur, that the institution would approve any research proposed by Dr Kaplan to test EmpowerPlus after the issues raised by Health Canada's comments on the Clinical Trial Application with this product suggests meaningful protection for the rights and welfare of research participants may receive short shrift at the institution.
Clinical Trial 12
L. Martin, B. Kaplan
TITLE: Potential clinical benefit of nutritional supplements in the management of fibromyalgia.
Publication: Martin L, Kaplan B. Potential clinical benefit of nutritional supplements in the management of fibromyalgia. The Journal of Musculoskeletal Pain. 1999;7(4):127-128.
There is no indication of REB approval in the Calgary research database.
Source: University of Calgary Cumulative Summary of Closed Protocols / No Entry. 2002-09-12. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_pre02.html
This is a case report of a single subject, of 13 months' duration from November 1997 to December 1998. Investigational products are described on p. 128:
The supplements included a multivitamin preparation with vitamins A, B1, B2, Niacin, B6, B12, C, D, E, Folic Acid, Pantothenic Acid, and Biotin; a mineral supplement in tablet form which included calcium, copper, chromium, iodide, iron, magnesium, manganese, molybdenum, nickel, potassium, selenium, tin, vanadium, and zinc; grape seed extract; a colloidal mineral supplement which contained trace amounts of all minerals from aluminum to zinc.
This is consistent with the combination of Melaleuca Inc., Body Systems Technologies, T.J. Clark Inc., products used in the pediatric ADHD study (Clinical Trial No. 1, above), and in fact the relationship between this case report and the ADHD study is described in the newsletter of the Alberta Heritage Foundation for Medical Research:
His colleague, attention deficit disorder (ADD) specialist and Heritage researcher Dr. Bonnie Kaplan, related that one of her associates had reported relief from fibromyalgia after taking a particular nutritional supplement that was being studied in attention deficit disorder. Intrigued, Dr. Martin and Dr. Kaplan decided to test the product on fibromyalgia patients in a research study.
Source: AHFMR Research News – Spring 2000. Accessed on 2004-05-17 from http://www.ahfmr.ab.ca/publications/newsletter/May2000/Spring00/fibro.feat.htm
Clinical Trial 13
L. Martin, B. Kaplan
TITLE: A Randomized Controlled Trial of a Nutrient Supplement in the Treatment of Fibromyalgia.
CHREB approval: June 16, 1999
Funding: (No. 14) Alberta Heritage Foundation for Medical Research (1998 competition)
99 subjects enrolled, 34 dropped out
Sources:
Nutraceutical Treatment of Mental Illness.1999-03-30. (Meleuca Inc., P.2.) Available from http://www.circare.org/FOIA/asraati_bjkappl2.pdf
Consent Form for this trial: University of Calgary Access Request 01-010 Disclosure. Kaplan BJ. Consent Form. A Randomized Controlled Trial of a Nutrient Supplement in the Treatment of Fibromyalgia. 2001-11-07. Available from http://www.circare.org/FOIA/uc_131_132.pdf
Presentation of this trial: Martin L, Kaplan B, Crawford S, et al. A randomized controlled trial of a nutrient supplement in the treatment of fibromyalgia. Program and Abstracts of the American College of Rheumatology 66th Annual Scientific Meeting. October 25-29, 2002. New Orleans, Louisiana. Abstract 1656. Available from http://www.abstractsonline.com/viewer/viewAbstract.asp?CKey={CEB4AC1A-858A-4949-9F52-766E9354A4BA}&MKey={413F3F7E-5615-4A10-8709-07B55AC25F69}+&UKey=&AKey={AA45DD66-F113-4CDD-8E62-01A05F613C0D}. Also available online via Medscape coverage of the presentation at the American College of Rheumatology 2002 Annual Meeting. Available from http://www.fibromyalgiasupport.com/library/showarticle.cfm/id/4178
The short version is that the trial demonstrated no evidence of efficacy in fibromyalgia, save for a decrease in the number of tender points between 6 and 9 months in the active group compared to the control group. Nevertheless the investigators concluded that the results of this study argue against nutritional deficiencies being a primary or important cause of FM.
Yet no there was no reason to suppose nutritional deficiencies
were a cause of fibromyalgia in the first place, and this study didn't test the subjects for nutritional deficiencies
prior to enrollment in the trial — are we missing something here?
The presentation abstract contains a number of unusual statements of such a sort as to cast doubt on the investigators' commitment to accurate reporting of scientific data. Specifically, the authors write:
The beneficial effects of a nutrient supplement called E.M.Power+ in the management of fibromyalgia (FM) was reported in a recently published case study (Martin & Kaplan, 1999). The supplement contains 36 ingredients: minerals, vitamins, amino acids, and antioxidants. A randomized, double-blind placebo-controlled trial was conducted to evaluate the supplement's efficacy in the treatment of FM.
This is perplexing indeed. The subject in the 1999 case study didn't take EmpowerPlus (no matter how it's spelled) because it didn't exist during the period recorded in the study (1997-98); the ingredients described (above) don't match EmpowerPlus; EmpowerPlus doesn't contain tin, listed as an ingredient in the 1999 study, and it appears self-evident that something with 36 ingredients cannot contain a colloidal mineral preparation,
which itself contains more than 70 elemental ingredients.
What's more, in 2002 University of Calgary records show this study was testing EmpowerPlus manufactured by Evince International, LLC. Yet in 1999 Dr. Kaplan represented to Alberta Innovation and Science that this study was testing products manufactured by Melaleuca Inc. You have to wonder who knew what and when.
Sources:
Nutraceutical Treatment of Mental Illness.1999-03-30. (Meleuca Inc., P.2.) Available from http://www.circare.org/FOIA/asraati_bjkappl2.pdf
The authors also write that:
All patients took 24 capsules of the supplements daily for 6 months, and were then invited to participate in an open label extension for 3 more months. Fifty of the patients continued in the open trial.
The invitation to continue in an open label extension likely caught research subjects by surprise because there was no mention of this in the consent form. If the Conjoint Health Research Ethics Board approved a protocol change, the consent form should have reflected this, and although our ATI request specified the most recent versions of the informed consent, because of this and other inconsistencies, we re-confirmed Calgary's understanding of our request and were reassured that we had the most recent version used in the trial.
Nearly one-third of the subjects dropped out of this trial, and if we assume that the similarity of reasons given for doing so (tummy troubles) indicates that the drop-outs were largely subjects taking the active drug, this suggests that EmpowerPlus at a dose of 24 capsules a day is intolerable or extremely unpleasant for a significant number of people. It also suggests that the higher dose of 32 capsules a day prescribed in the psychiatric studies may have been even less tolerable to subjects, especially to the pediatric subjects taking this same dose of 32 capsules.
Finally, at some point during the summer of 2003 the entry for this clinical trial went missing from the University of Calgary's research database. It's extremely disconcerting to think that a clinical trial could disappear from permanent university records. To date, the trial remains unpublished.
Source: University of Calgary Cumulative Summary of Closed Protocols / No Entry. 2002-09-12. Available from http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_pre02.html
Dr. Kaplan, however, lists the $36,000 grant for this study that she shared with Dr. Liam Martin in her curriculum vitae. Curriculum Vitae of Bonnie J. Kaplan Ph.D. 2005. P.6. Available from http://www.danoneinstitute-can.com/pdf_files/cv/bonnie_kaplan.pdf
Last Updated: 2009-04-06
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