Design and Conduct of Clinical Trials 2016

Sheffield Kidney Institute
Prof Meguid El Nahas, MD, PhD, FRCP
Professor of Nephrology & Chairman
Global Kidney Academy
Sheffield, UK
How to:
1. Design and Conduct a Clinical trial
2. How to Report it
3. How to Appraise it
2000 2016

• Ethical Issues: …Declaration of…..?!
• Trial Design/Protocol…
• Trial Conduct:…G… P?!
• Statistical analysis…what is power?
• Results: NNT…?
• Interpretation
• Conclusions

Ethical Issues
The Declaration of … Helsinky
• Nuremberg Code 1947
• WMA: Declaration of Helsinky 1964
• Tokyo 1975
• Venice 1983
• Hong Kong 1989
• South Africa 1996
• Edinburgh 2000

Declaration of Helsinky
• Protection of patients rights
• Informed consent
• Independent approval
• Scientific/medical basis
• Appropriate risk: benefit ratio
• Subject well being takes precedence over other considerations

• Ethical Issues: …Declaration of Helsinky
• Trial Conduct:…G… P?!
• Statistical analysis…what is power?
• Interpretation
• Conclusions

How to:
BP Control in CKD
Standard v Intensive BP Control
Rational
Design/Protocol
Conduct
Results
Interpretation

How to:
BP Control in CKD
Rational/Scientific Question
“Whether Intensive BP Control benefits CKD patients ?”

Aim of the study
• To determine the impact of
Intensive <120/80mmHg v Standard <140/90mmHg
• 1. Primary Endpoint:
– CKD Survival
– Combined Patient and Renal Survival
• 2. Secondary Endpoints:
– Reduction in MACEs
– Combined Death, CHF and CVD MACEs
– Proteinuria reduction

How to:
BP Control in CKD
Design
What is Standard v Intensive?
Endpoints
How to Measure BP…?!
Sample Size
Duration of the Observation
DMSB

Trial Design
• Ecological studies
• Case-Control studies
– Retrospective analysis
• Cohort studies
• Observational studies
• Randomised Prospective controlled trial (RCT)
• Active control
• Placebo control
• Parallel/Cross-over

Sample size estimation
• 1. Expected difference between groups (~20%)
• 2. Power (probability of NOT getting a false negative result) (80%)
• 3. Level of statistical difference (p value = probability that we have a
False Positive) (<5%)

Trial Protocol
• Background
• Aim
• Inclusion and Exclusion criteria
• Primary/secondary end-points
• Parameters
• Documentation (CRF)
• Monitoring
• Statistical analysis
• Reporting

Informed Consent
• Has to be taken by PI
• PIL
• Sit with patient and Discuss
• Give Benefit and Risks of Study
• Give the patient time to decide
• Come back and Discuss and answer any questions
• Discuss with family
• Patient signature and PI signature/date

• Trial Conduct: …G…P
• Statistical analysis: what is power: 80%
• Interpretation
• Conclusions

How to:
BP Control in CKD
Conduct
GCP

What is GCP?
Good Clinical Practice

ICH- Good Clinical Practice (GCP)
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses and
reporting of clinical trials that provides assurance
that the data and reported results are credible
and accurate, and that the rights, integrity, and
confidentiality of trial subjects are protected

Principles of IH-GCP I
• Anticipated benefits to the subject, science and society
justify the risks/inconveniences
• Scientifically sound, clear and detailed protocol
• Adequate pre-clinical and clinical data (pre-trial
regulatory approval)
• Pre-trial Ethics Committee approval

Principles of ICH-GCP II
• Freely given consent prior to trial
• Medical care given by qualified doctor/dentist
• Suitably trained staff
• Trial supplies manufactured, handled and stored according
to GMP
• Data management systems accurate
• Confidentiality of records
• Quality assurance of every aspect of the trial

• Trial Conduct: GCP
• Statistical analysis: what is power: 80%
• Interpretation
• Conclusions

How to:
BP Control in CKD
Results
Blinded Analysis…
Statistical Honesty…

How to:
BP Control in CKD
Interpretation
Facts are Facts
Don’t Overinterpret
Don’t Overspeculate

NNT
The difference between:
STATISTICAL Significance
&
CLINICAL Significance

The Trial
is
Negative!

The Trial is
Negative…
Let me Fix
that…!

Results
Negative Results are as Valuable as Positive Results
(DON’T FIX…)

The Trial is
Negative!
Lets
Report it!

Reporting Results of a Clinical Study
Local Presentation
National Presentation
International Presentation
Peer Reviewed Publication

The Abstract
• 150 words unstructured
• 250 words structured
• 2-3 lines introduction
• Aim
• Material and Methods (Procedures)
• Main Results including data and statistics
• Conclusion

Abstract
• Give summary of results with data and stats
• Do not tell a Story….Give Facts
• Always re-read and Spell check!

Abstract
This study….

Presentation Tips
1. Be Presentable
2. Be Confident
3. Speak Clearly and Face the Audience
4. Make Contact with the Audience
5. Look and Point at Key features of your slides
6. Don’t read the slides unless the audience is blind…
7. 1 slide/minute
8. Don’t crowd the slides
9. Take your time, don’t Rush
10. Conclude by thanking the audience for its attention

Results
This study showed that by an intensive control of the BP we failed
to imrpove a range of MACEs including strokes but there was an
overall benefical effect on mortality and in particular a reduction in
heart failure that may have impacts on the overall CVD outcomes as
well as on patients survival.
However, the progression of CKD was not slowed, except if we
look at some high risk subgroups where there may be a marginal
effect on CKD progression. Having said that, it is noteworthy that
proteinurea was not affected. Also great caution about the increased
incidence of CKD and that of AKI in the patients on intensive BP
control.

Results
Intensive BP:
• Mortality Improved
• Combined renal and CVD endpoints improved
• Heart Failure improved
• No improvement in MACEs including strokes
• Progression of CKD was not slowed
• Proteinuria was not affected
• incidence of CKD and AKI increased

How to write a paper
• The Title
• The Abstract
• The Introduction
• Material and Methods
• Results
• Discussion
• References

How to Write a Paper
The Title
• Attractive
• Informative
• Relevant
• Realistic
• Not too long/ Not too short

BP Standard v Intensive
Intensive BP Control in CKD
Intensive BP control and the Progression of CKD
Intensive BP control slows the progression of CKD in younger
patients but has borderline effects in the elderly, but has no
effect on proteinuria

The Authorship
• Fair
• Comprehensive
• Appropriate

The Introduction
• Key references
• Relevance to current study
• Justification and rationale of the study
• Aim of current study
• Avoid a lengthy review of the literature

Justification/Rationale of the study
It is generally accepted that poor blood pressure control accelerates the
progression of CKD
JNCVIII suggest target BP <140/80 mmHg
We aimed to determine whether lower BP level(s) increase benefit(s)

Aim of the study
• To determine the impact of
Intensive (<120/80mmHg) v Standard <140/90mmHg
• 1. Primary Endpoint: Combined Patient and Renal Survival
• 2. Secondary endpoints:
– Combined Death, CHF and CVD MACEs
– Proteinuria reduction

The Methodology
• Describe the population studied
• Detail inclusion and exclusion criteria
• Detail the experimental protocol
• Refer to establish methods
• Describe new or modified methods
• Ethics committee approval
• Helsinky Declaration
• Statistical analysis

The Results
• Make your presentation logical
• Start with general observations
• Divide your results into sections
• Do not leave results out
• Avoid data presentation repetition: use either text, tables,
figures but don’t repeat yourself

Results
• Intensive BP improved outcomes; Patients and Renal Death reduction
• 32 of 44 on Intensive BP therapy showed an improvement in Heart
Failure, compared to 21 of 46 on standard BP levels (Figure 1)
• Proteinuria was not reduced
• Heart Failure, MACEs and Death Improved

The Discussion
• Summarise important findings
• Explain your findings
• Compare your findings with the literature
• Explain disagreements
• Avoid too much speculation
• Acknowledge your study limitations
• Suggest further studies

Conclusion
Intensive BP control reduces mortality as well as Renal
and Cardiovascular Endpoints in CKD

Introduction/ Literature Review
COPY & PASTE
PLAGIARISM
Perfect english
Discussion
Own english…!!!!

Acknowledgments
• Individuals
• Funding

Acknowledgements
The authors would like to acknowledge the support they received from
ISN for their research
The authors declare absence of conflict of interest

References
• Vancouver style
• Authors. Journal year; volume: pages.
• Be consistent in your abbreviations
• Use conventional journal titles abbreviations

• You are as good as your last paper!!!!
• Pay attention to details big and small…!!!
• Make 10 drafts before submission….!!!!
• And then read once more….

The 5 Whats
1. What is the Rational of the Study
2. What is the Validity of the Results
3. What is the Utility/Usefulness of the Results
4. What is the Risk v Benefit of the Intervention
5. What is the Cost v Benefit of the Intervention

The 5 Whats
1. What is the Rational of the Study: OK
2. What is the Validity of the Results:
Increased diuretics decrease Oedema/Heart Failure
Intensive BP control has no impact on MACEs, CKD
3. What is the Utility/Usefulness of the Results:
Useless in CKD
4. What is the Risk v Benefit of the Intervention:
Increases AKI and incident CKD
5. What is the Cost v Benefit of the Intervention: High

https://www.youtube.com/watch?v=OGWniRyuvVA&feature=share

How to:
2. How to Report it
3. How to Appraise it

Design and Conduct of Clinical Trials 2016

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