Title: DreamTel; Diabetes Risk Evaluation and Management Tele-monitoring Study

Transcription

1 Author's response to reviews Title: DreamTel; Diabetes Risk Evaluation and Management Tele-monitoring Study Authors: Sheldon Tobe Joan Wentworth Laurie Ironstand Susan Hartman Jackie Hoppe Judi Whiting Janice Kennedy Colin McAllister Alex Kiss Nancy Perkins Lloyd Vincent George Pylypchuk Version: 5 Date: 14 March 2009 Author's response to reviews: see over

2 Title: DreamTel; Diabetes Risk Evaluation and Management Tele-monitoring Study Version: 4 Date: 22 December 2008 Reviewer: Dereck Hunt Reviewer's report: Major Compulsory Revisions: Abstract: The abstract has been improved significantly compared with the initial abstract. The authors may wish to amend sentence three of the second paragraph to indicate the duration of Phases 2 and 3. Page 3 paragraph 1: The authors should change the first occurrence of the word is to the word indicates in line 7. In line 10, the authors may wish to remove the capital letters used in the term people with diabetes. In line 13, the authors should add a comma after reference 3. In line 14, the authors may wish to add the word optimal after the word the. In line 15, the authors suggest that the ADVANCE study demonstrated a reduction in macrovascular events with normalization of the HbA1c below 7.0%. In fact, the ADVANCE study did not demonstrate any reduction in macrovascular events. Thank you for the extensive and very helpful review. The following changes have been made. The fourth sentence has been amended to indicate the duration of the phases: In the second and third phases lasting 18 months, The changes have been made as described. The following has been changed to better reflect the ADVANCED study. While the ADVANCE study demonstrated a reduction of microvascular but no significant reduction of macrovascular events with normalization of A1c to below 7.0%[4], the ACCORD study also targeting normalization of A1c below 7.0% found an elevated mortality and no reduction of cardiovascular events[5].

3 Page 3 paragraph 2: The first sentence in this paragraph is an important topic. It does not, however, relate to the material that follows subsequently in this paragraph. It is in fact an isolated concept. In line 4 of this paragraph, the authors should add a comma after the phrase for those who develop diabetes. A period needs to be added after the initial reference to reference 7. Further down in the same paragraph, the authors may wish to indicate the actual distance that separates the diabetes education centre in Edmonton from individuals living in northern Saskatchewan. Page 4 paragraph 1: In line 12 of paragraph 1, the word the should be changed to the words use of. Page 5 paragraph 2: The paragraph addressing the pathophysiologic consequences of diabetes is in fact somewhat repetitive as many of these issues have in fact been addressed earlier in the paper. Page 5 paragraph 3: The material related to the definition of a severe hypoglycemic episode, currently in lines 14 and 15, should be moved to earlier in the sentence. The first sentence has been moved to the end of the paragraph in the paragraph titled: Diabetes, First Nations and Kidney Disease Distance indicated in time needed to drive (over 3 hours). Use of substituted. The following sentences were removed and the paragraph joined to the previous one. The pathophysiological consequences of diabetes can be divided into microvascular (e.g. retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) disease. Hyperglycemia is felt to contribute to these diabetic complications by multiple mechanisms. The sentence has been changed as follows: Despite lower blood glucose levels attained in the intensive treatment group, there were fewer major hypoglycemic complications (eg. impaired consciousness which required help from another person) in the intensive treatment compared to the control group (just under 1% vs. 2% per

4 patient year respectively). Page 6 paragraph 1: The comma can be removed from the first line in the sentence after the word services. In line 8 of the paragraph, a comma should be inserted after the word Cree. Page 6 paragraph 3: The authors may wish to number the items in the list highlighting the ways in which the home care program has been augmented over the last three years. In line 11 of the paragraph, the word refer should be changed to referred, to indicate the past tense. Similarly, the word advocate should be changed to advocated. Line 21 represents a very new concept, and I would suggest that it would be appropriate to begin a new paragraph at this stage. Page 7 paragraph 1: In line 12, the authors may wish to reword the sentence so that it reads Blue tooth enabled glucose meters facilitate the downloading of the results to a secure electronic format. done The items were not numbered. Other changes made as suggested. Done as suggested.

5 Page 7 paragraph 3: Throughout this paragraph, the past tense has been used. This suggests that in fact the various activities of phase 1, 2 and 3 have in fact already been completed. Should this paragraph not be reworded using the future tense? Page 7- paragraph 4: In the first line of the paragraph discussing the experimental design, the past tense is used. Should this not be changed to the future tense? Page 8 paragraph 1: Once again in this paragraph, and in the paragraphs that follow on this page, the past tense has been used. This makes it difficult to be certain as to which activities have in fact already been completed and which activities are planned as part of the current protocol. Page 8 paragraph 3: In line 5, the authors may wish to change the word developed to the word delivered. In line 6, the authors may wish to change the word response to the word impression. In line 7, the initial use of the word the should be removed. With respect to the same sentence, are there any details regarding the questionnaires that were used to assess participants impressions of the Thank you. This paragraph was changed to the future tense to reflect the fact that this is a study protocol. This has been changed to the future tense. This has been changed to the future tense for the activities that were planned as part of the protocol. Changes made as suggested. The sentence about the frequency of the patients response to the questionnaires has been removed.

6 teleprompt system? In line 8 of the paragraph, the authors note that the frequency of the patients response to the questionnaires was recorded. It is unclear as to whether the authors are referring to the questionnaires or to the actual teleprompts themselves. Page 8 paragraph 4: In the first line, the authors may wish to begin the sentence with the words another objective for instead of the words the plan for. In line 2, there should be a comma before the word noting. In this paragraph overall, it is unclear exactly which results are going to be compared, given the fact that there will be results in the patients meter memory, as well as results in the patients logbooks, and results on the central server. Additionally, it is unclear who will be completing this activity. Will this be completed by the home care nurse? Page 9 paragraph 1: In the last sentence the authors note that the frequency of participants ability to generate a result will be calculated. Are they referring to the participants ability to This paragraph has been changed and shortened to the following to improve clarity. This analysis will be completed by the statistician. Another objective for the first three months of use is to compare denominated data from three different sources; data transmitted by the device and stored on the web site, data stored on the device itself and the patient s log book, noting discordant values. Data is to be presented as the proportion of results recorded accurately. The frequency of monitoring based on data from the electronic output is to be assessed for the entire period. See paragraph above.

7 complete a glucose measurement and download this to the server? Page 9 paragraph 2: In the title for Phase 2, the authors include the terms and implementation. Should these words in fact be removed as the implementation is in fact part of Phase 3. For the discussion of Phase 2 in general, it is unclear as to how much of the work described has in fact already been completed, and how much of the work is in fact part of the current protocol. For example, it would appear that the algorithm for medication introduction and adjustment has already been developed, but still needs to be reviewed with local practitioners and experts. Thank you, this change was made. These paragraphs were revised to clarify that the algorithms had been developed and would be reviewed with the local physicians prior to initiating the study. The following paragraph was revised to reflect this. Algorithms developed for diabetes management were developed based on clinical practice guidelines and reviewed with experts in diabetes management. For self monitoring of blood glucose[1], the goal is a minimum of four times daily, two days per week for those on or starting insulin. Medication will be introduced in a stepped fashion for those on diet therapy alone starting with metformin followed by a sulphonylurea (gliclazide, as it is better tolerated in patients that develop kidney disease than others)[53], thiozolidendiones (TZD s) will be added if sulphonylureas have failed. Pioglitazone (Actos) was chosen for use as it is a once daily preparation. This step was added prior to the controversy over rosiglitazone[54]. The algorithm for diabetes intensification to be carried out by the Home Care team was incorporated into a standardized order form for the primary care physician to approve. The study team in partnership with the primary care physician will be

8 responsible for assessing contraindications to the algorithms. Page 9 paragraph 2: In the first paragraph under Phase 2, the authors note that thiazolidinediones will be added if sulfonylureas have failed. Would it be correct to say that the primary care practitioners will be responsible for assessing contraindications to the thiazolidinediones? Page 9 paragraph 3: Once again, there is a range of verb tenses used in this paragraph, making it unclear as to which activities have been completed and which will be completed in the future. The final sentence should be rewritten as it is somewhat unclear at present and lacks necessary punctuation. Page 9 paragraph 4: The verb tense in the first line should be the future tense. See above paragraph. Thank you, these changes have been made. These changes have been made.

9 Page 9 paragraph 5: The first four sentences in this paragraph in fact refer to Phase 1 of the study and are currently out of place. The balance of the paragraph appears to relate to activities that form part of Phase 3 of the study protocol. In line 7, the verb tense should be the future tense. In line 8, the authors indicate that at the intake into the study, clinic patients willing to participate will receive a physical examination and an assessment of their current diabetes status. The protocol does not indicate, however, as to whether this will occur at the beginning of Phase 1 or Phase 3. Page 10 paragraph 2: In the first line, the authors make reference to Appendix B. It is interesting that no reference was made earlier in the manuscript to Appendix A. At the end of line 1, I would also suggest that a colon be used instead of a period. In line 5 of the paragraph, the authors should be explicit as to which Phase they are referring to. I take it that they are in fact referring to enrolment into Phase 3 of the study. With respect to the entire paragraph, my sense is that it would be helpful to move the paragraph so that it is located after the first paragraph in the discussion of Phase The first four sentences were moved earlier into the section on phase 1. The verb tense has been changed. The timing of the physical exam being in phase 3 has been clarified. Appendix A is now referred to on page 13 under the approvals paragraph. The changes have been made and the paragraph moved to the discussion of phase 2, now on page 9.

10 2. In line 14 of the paragraph, a comma should be inserted after the first clause. Page 10 paragraph 3: In line 2, the word include should be changed to the future tense. In addition, the word rational should be changed to rationale. Page 10 paragraph 4: Once again there is the issue of the verb tense. It is unclear as to whether the home care referrals have in fact already been developed or if they will be developed as part of Phase 2. In line 4 of the paragraph, the authors refer to following those patients whose family physicians do not wish to be part of the study in an intent to treat manner. Would it not be better to refer to this group as a control group? With regard to these control patients, will information regarding diabetes clinic referrals be collected? Will these patients be allowed to use their blue tooth enabled glucose meters, and if so, will the downloaded values be Changes made. The home care referral forms were already developed prior to the study being started. The issue of the intent to treat was revised as suggested. Home care referral forms were developed for the primary care physicians. It was planned that if the primary care physician did not want the Home Care team to do the intensification of diabetes management according to the planned algorithm that the subjects would be followed as a control. If the primary care physician directs the Home Care team to manage the patients in a similar fashion, only using different medications from the algorithm, based on patient specific factors, these patients will remain in the study. Referrals to the local diabetes education centre will be tracked if any occur. The commencement date for intensification will be recorded. Intensification is defined as increasing the dosage of a medication, adding another

11 forwarded to the primary care providers? With regard to Phase 2 in general, it is unclear as to how long Phase 2 is envisioned to last, or if this is somewhat open-ended based on the rate at which its goals are achieved? medication or initializing insulin according the algorithm for intensification. Phase 2 was completed within three months of initiating the study. Page 11 paragraph 2: The rationale provided in the first paragraph under Phase 3 is in fact the rationale for the entire DreamTel project, rather than the rationale for Phase 3 specifically. The material in this paragraph should be blended into the first paragraph of the background on page 3. In the current paragraph, the authors appropriately indicate that the UKPDS study suggested a 25% reduction in the risk of myocardial infarction for every 1% reduction in HbA1c. In the subsequent sentence, however, the authors state that this finding is consistent with the ADVANCE study. This is not the case as the ADVANCE trial did not demonstrate Thank you. This paragraph was moved into the background section on page 3. The following was added instead for the rational. Based on the success of the DREAM study where a chronic disease management model resulted in improved blood pressure control 7, the DreamTel study hopes to demonstrate that a chonic disease management program can improve glycemic control in First Nations People with diabetes. Page 5 Intensification of diabetes management. The paragraph has been moved to this section. There is now evidence in both type 1 as well as type 2 44 diabetes, that improved glycemic control will reduce the microvascular complications of diabetes. An epidemiologic analysis of the UKPDS 45 showed that there is no threshold for benefit when it comes to glucose lowering, and that any reduction in A1c is associated with reduced risks for both micro- and macrovascular disease. In their analysis, every 1% decrease in A1c was associated with a 25% reduction in

12 any reduction in macrovascular events with improvement in glucose levels. It would be appropriate for the authors to provide a paragraph describing the overall rationale and purpose for Phase 3 of the study. risk for myocardial infarction 45. The ADVANCE study demonstrated a reduction of microvascular events with normalization of A1c to below 7.0% 4. Evidence for caution in the way that diabetes intensification is achieved comes from The ACCORD study which targeting aggressive normalization of A1c in patients with longstanding diabetes and found an elevated mortality 5. The goal of diabetes intensification therefore is to reduce the risk for the complications of diabetes by controlling blood glucose safely. Page 11 paragraph 4: In the first line of paragraph 4, the authors note that Phase 3 is designed as a pilot study involving 50 subjects. If significantly fewer than 50 individuals successfully complete Phase 1 of the study, will the plan be to recruit additional individuals into Phase 1 so that 50 subjects will be included in the pilot study? If so, this should be indicated in the protocol. Page 11 paragraph 4: In line 1 of paragraph 4, the word Phase has been misspelled as hase. In line 2, the word will should be added in before the word have. In the final line of the paragraph, the words are drawn should be changed to will be drawn. The following was added to that paragraph to explain what would happen should significantly fewer subjects be enrolled into phase 3. If fewer subjects than anticipated make it through phase 1 and are eligible for phase 3, additional subjects will not be recruited. As this is a pilot study, the reasons that fewer subjects than expected are able or willing to enroll into phase three will be explored. Changes made

13 Page 11 paragraph 5: The future tense should be used in this paragraph. Page 12 paragraph 4: In the first line, the authors note that the inclusion criteria for Phase 3 will include individuals with HbA1c > 7.0%. Have the authors intentionally set a different HbA1c cutoff for Phase 3 in contrast to Phase 1? For Phase 1, the HbA1c cutoff was noted to be 7.4% (see page 8, line 1). Page 12 paragraph 5: The authors should put a comma after the word compare in line 2. Further in the same paragraph, the authors note that another goal will be to determine the ability of individuals to maintain an 80% adherence rate to the recommended glucose self-monitoring frequency. Is this a goal of Phase 3 as well as being a goal of Phase 1? Changes made as suggested. Thank you for finding this discrepancy. The original protocol had a level of 7.4% but this was lowered to 7.0% as an amendment because of difficulty finding sufficient numbers of people with uncontrolled blood glucose in the community. The change was made to page 8 line 1 to make it 7.0% as well. The ability to maintain self monitored blood glucose is also a goal of phase 3. This has been indicated in this paragraph for clarification. Analytic Procedures and Sample Size Calculation. This is a pilot study that will compare, in a before and after methodology, the intervention of diabetes intensification on the primary response variable of blood glucose level (A1c) measured at baseline and at 6 months. The pilot study will also determine the ability to enroll patients into the study and determine how many are able to maintain an 80% adherence rate to the use of the glucose meter four times daily at least twice weekly. This is also a goal of phase 3 of this study. See Appendix C for statistical design considerations.

14 Page 12 paragraph 7: In this paragraph, the authors note that patients will be asked to note any adverse events. The protocol does not, however, specify which events will be included. It does imply that hypoglycemic evidence will be included. It is not clear, however, whether other events such as hospitalizations or myocardial infarctions, etc., will be included. Page 13 paragraph 1: In the first line, the word severe should be inserted before the word hypoglycemia. Will other medication use during Phase 3 of the study also be tracked (for example: ACE inhibitor use, statin use, etc.)? Will physician visits be tracked? Page 13 paragraph 4: The authors note that participants will be followed for 18 months from the study entry. The authors should be explicit as to whether they are referring to study entry into Phase 1 or Phase 3. This paragraph has been clarified to indicate that the adverse events relate to hypoglycemic episodes only. Safety and Interim Monitoring. Drug therapy may be interrupted at any time during the trial if further evidence for more appropriate drug therapy becomes available. All drugs used in this trial are available in regular clinical practice. Women of child-bearing potential must have a negative urine pregnancy test prior to receiving study medication. Patients will be asked for adverse events from the last visit related to hypoglycemic episodes and these data recorded. In the UKPDS 33 study the rates of major hypoglycemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin 48;49. Hypoglycemia defined as needing the assistance of another person, or coma, will be tracked, as will diaryrecorded instances. Corrections made as suggested. Other medication use and physician visits will not be tracked due to resource constraints. The sentence was changed to clarify the study duration. Study subjects will be followed from study entry until study completion (18 month study protocol from the start of phase 1).

15 Page 22: The authors may wish to make reference to Appendix A in the body of the text. Page 28: In the second paragraph, reference is made to Appendix A. Clearly, however, the Appendix A being referred to on page 28 is in fact not the same Appendix A currently in the manuscript. Page 30: Reference is made to Appendix B (a sample consultation sheet), and to Appendix C (a sample order sheet). These appendices have not been included with the manuscript. Done. Page 13, under Analytic Procedures and sample size correction section. The reference to appendix A has been removed. These references have been removed as they refer to appendices that were not included in the manuscript.