MODULE 3 ASSIGNMENT

SUBMITTED BY: ANSARI A CRANFIELD REGISTRATION NUMBER: 048330 ICRI NUMBER: M- 635 ICRI MUMBAI CAMPUS

CONTENTS

PART- 1 Summary of study designs 1. Introduction..1 2. Efficacy of hormone replacement therapy...1 3. Safety of hormone replacement therapy..2 4. Conclusion...................3 5. Critique on study design. ....3

PART- 2 Develop a study design for a new treatment 1. Introduction.................................6 2. Summary of potential designs.....7 3. Preferred study design....10 4. References .11

PART-1

Summary of study designs

Introduction
Menopause is characterized by low levels of sex hormones (estrogen and progesterone) and is associated with symptoms like hot flashes, depression, weight gain, hip fractures in the women.4 Different types of HRTs are available in the market such as- combined estrogen and progestin HRT (CHRT), estrogen replacement therapy (ERT), conjugated equine estrogen (CEE), progestin alone HRT, equine estrogen, ethinyl estradiol, oral contraceptives, tibolone and other type of HRTs which are useful in the management of menopausal symptoms in women. 1-3

Efficacy of hormone replacement therapy

ERT is more likely to be used in the management of postmenopausal symptoms in women with prior hysterectomy.1 CHRT has efficacy to manage the symptoms of post menopause who has intact uterus.1 Estrogen therapy has efficacy to relieve from vasomotor symptoms and vaginal atrophy.3 Estrogen therapy is useful to treat as well as to prevent the osteoporosis.3 HRT masks the menopausal status in the women if used before the natural menopause.2 Estrogen therapy is useful to manage symptoms associated with postmenopausal status in > 60 years old women.3 Estrogen therapy reduces the risk of coronary events from 30% to 50%.3 Combined Estrogenprogestin is effective in treating the colorectal cancer, hip fracture and other fractures.3 CEE has efficacy to reduce the risks of coronary heart disease, invasive breast cancer, hip fractures and

vertebral fractures.3 CEE is approved by the USFDA to get symptomatic relief in post menopausal women with lower effective dose for feasible short term use.3 Ever use of HRT has efficacy to manage symptoms of postmenopausal women rather than premenopausal or perimenopausal women.2

Safety of hormone replacement therapy

Continuous use of progestagen has higher risk of breast cancer than in sequential use.1 Use of combined HRT( sequential or continuous) and progestagen alone increase the risk of breast cancer if used for 5 years.2 Use of CHRT increases the risk of ER+/PR+ breast cancer rather than risk of ER+/PR or ER/PR breast cancer.1 Use of CHRT has higher risk of breast cancer than ERT.1 Women within age group of 55-65 years are at higher risk of breast cancer who used HRT for 10 years.2 Thinner women have high risk of breast cancer with HRT use.2 Mortality rate of HRT associated risk of breast cancer is still not clear.2 The risk of breast cancer with the use of different types of HRT mentioned here in the descending manner- combined estrogenprogestagen therapy > tibolone HRT > other unknown types > estrogen alone HRT.2 CHRT and oral contraceptives increase the risk of developing invasive lobular cancer (ILC) than invasive ductal cancer (IDC) if used for 5 years.1 Users of ERT are at higher risk of endometrial cancer if used for 10 years.1, 2 Use of HRT is not safe with alcohol consumption in postmenopausal condition.1 Use of CEE has been linked with higher risk of non fatal stroke, venous thromboembolic disease and colorectal cancer than invasive breast cancer in the post menopausal women.3 Mortality rate is not increased in postmenopausal women with the use of CEE.3 CEE is not safe for

postmenopausal women in the age group of 70-79 years.3 CEE is not useful in the management of chronic postmenopausal status in the women.3

Conclusion
The safety and efficacy of HRT depend on the status of menopause, age of women, course duration, body index, alcohol consumption and also depend on preparations, doses, and routes of administration, alone therapy, combined therapy and sequential or continuous use of HRT.1-3 HRT is useful in postmenopausal women who has intact uterus or hysterectomy.1 HRT is useful to provide relief from vaginal atrophy, vasomotor symptoms and also prevent or treat the osteoporosis in postmenopausal women.3 HRT reduces the risk of coronary heart disease, hip fractures and vertebral fractures.3 HRT has some risks which aroused in postmenopausal women, such as- endometrial cancer, non fatal stroke, venous thromboembolic disease, colorectal cancer, invasive lobular cancer and invasive ductal cancer. It also shows high incidence of breast cancer in thinner postmenopausal women.1-3 Finally conclude that safety and efficacy of HRT is debatable in menopausal condition. It needs more consideration and it should be further studied.

Critique of study design

A case control study: To evaluate the kinship amongst long durations and dissimilar regimens of hormone therapy and risk of breast cancer the population based case control study is very effective.1 Case control study is the observational study and also retrospective study.

This study design is beneficial for rare outcomes such as risk of invasive lobular, ductal, ER+/PR- , ER+/PR+ and ER-/PR- breast carcinomas with the use of HRT in postmenopausal.1 Selection of Health care financing administration (HCFA) record to make easy for enrolling cases of breast cancer from the region of Washington and it is also easy to enroll controls with the help of HCFA record.1 This study design is very effective in those diseases which have long response time periods. The study design containing different types of preparations and duration of use of regimens such as estrogen replacement therapy (ERT), combined estrogen and progestin hormone replacement therapy (CHRT), continuous and sequential CHRT, long term and short term use of these regimens were evaluated to obtain authentic exposure.1 To identify factual exposure, the cases were further divided in invasive lobular cancer (ILC) and invasive ductal cancer (IDC) groups.1 The study protocol got approval from Fred Hutchinson Cancer Research Center Institutional Review Board. Written informed consent was taken from all study participants to conduct the study continuously without any type of violation.1 On the basis of standardized integrated questionnaire they obtained demographic characteristics and risk factors for women.1 Baseline characteristics of the control group and cases were similar which reduced the problems such as under matching and over matching.1 A cohort study: For the observational study in large population cohort study is very effective.2 Large sample size is the major drawback of this study design which takes longer time of period.2 The subjects were recruited by National Health Service Breast Screening Programme (NHSBSP)

with strict inclusion and exclusion criteria which took long period of time (approximately 4 years).2 The baseline characteristics of each subjects mentioned clearly to minimize the confusion in the measuring of one or more outcomes.2 By this study design we can measure, association between different exposures and outcome.2 The use of HRT was unbiased by recording of incident and fatal breast cancer on the basis of International Classification of Disease.2 The subjects were subdivided on the basis of lengthy stratified randomization method which create problems to evaluate the statistical analysis2 but with the help of STATA computing package (version 7.0) evaluation of statistical analysis became very easy.2 A randomized controlled trial: The study design was single parallel, randomized, double blind, placebo controlled disease prevention trial which was used to assess the effect of conjugated equine estrogen (CEE) in postmenopausal women with hysterectomy.3 Randomized controlled trial known as an experimental study.5 To assess the safety of HRT it is mandatory to use parallel design because it is a long term study. The study was done in multicentre to conduct the study in different region in genetically variant patients to obtain accurate result and also to reduce problem which arise in recruiting more than 10000 postmenopausal women at one center.3, 5 The subjects were recruited with age group in between of 50-79 years which showed the violation with age group but the study design obtained approval from the Institutional Review

Board and also obtained informed consent from subjects to avoid informed consent process associated violation.3, 5 The trial design used only single dose and one oral preparation of estrogen to the subjects but did not use different types of preparation, doses and different routes of administration of the interventional drug to evaluate the accurate result.3, 5 The health risks and benefits with use of estrogen alone were assessed by the independent Data and Safety Monitoring Board (DSMB) to obtain authentic results.3 To get same baseline characteristic of the subjects they provided 3 months of washout period before screening for the recruitment which reduced the complexity of the subjects past medication.3, 5 The statistical analysis measured by SAS (version 9.0) and significance set at the 0.05 level to evaluate the accurate data.3

PART-2 Develop a study design for a new treatment

Introduction
The testntone compound developed by X-company (a chemical supplier) who wants to get effective and potential clinical study design for evaluating activity of testntone compound in male andropause. To make effective and potential study design it is mandatory to know about andropause and risk-benefit ratio associated with currently available treatment of andropause. Low levels of serum testosterone in male is clinically termed as hypogonadism.6 Hypogonadism known as andropause in the aging male.6 The signs and symptoms associated with andropause
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are decreased sexual urge, erectile disfunction, decrease in muscle mass, reduced bone tightness, diminished sense of energy, anemia and depression.6 Approximately 2 to 4 million men are affected with Hypogonadism in United States and risk of Hypogonadism increases constantly in the population with age increase.6 Although testosterone replacement therapy has efficacy to improve all signs and symptoms of andropause, some risk factors arise with this therapy such as cardiovascular disease, erythrocytosis, lipid alterations, prostate cancer, fluid retention, sleep apnea, hepatotoxicity, oily skin or acne, benign prostatic hyperplasia, infertility etc.6 There are no long term and long scale studies done yet to evaluate the risks and benefits of testosterone replacement therapy in andropause because there is anticipated high risk of prostate cancer with testosterone replacement therapy.6

Summary of potential designs

There are different types of study designs used to conduct a clinical trial but in those the parallel and crossover designs play an important role to evaluate the effects of testntone in andropause. One question is arising in mind is that, why these designs are potential for the testntone trial? Well, it is briefly discussed here. 1. Parallel group design: After screening method and strict inclusion and exclusion criteria patients are recruited for the study. Subjects are randomly divided into two or more groups.5 Each group is receiving same treatment in whole study duration without any washout period.5 Example of parallel design which is useful for new compound testntone for andropause is randomized, double blind, placebo-control, parallel design.
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Advantages of study design

Disadvantages of study design

1. Many times placebo controlled trial is more 1. The major problem is that it requires large preferred over active control, as here standard number of patients for the study. therapy available has lot of adverse effects, putting patients at more higher risk 2. It is useful to compare the effect of multiple 2. It shows high variability of data when doses of testntone against disease. compared with crossover studies.

3. It is useful to evaluate that there is 3. It is very long study thats why it becomes improvement with testntone or not by expensive. introducing placebo control in parallel design. 4. By providing long term duration study it 4. Design is not suitable for rare disease shows accurate results which are arise in conditions. controversial risks. 5. It provides statistical data in the large 5. Some times ethical problem arise with

number of subjects which become very easy to placebo control trial which may led to delay in analyze. marketing of testntone.

2. Cross over design: Subjects are divided into two or more groups on the basis of randomization.5 All groups are receiving two or more treatment by providing washout period in interval between two different treatments received by subjects.5 Washout period is basically provided to subjects for returning the baseline status of each group and then use another treatment.5

Example of crossover design for new compound testntone in andropause is randomized, double blind, active control, crossover design. Advantages of study design Disadvantages of study design

1. This study design requires fewer patients for 1. It shows high complex statistical data which the andropause. become difficult to evaluate.

2. Active drug and testntone are evaluated in 2. Poor patient compliance as more study visits same subject group. required.

3. This study design is less expensive as 3. It is difficult to evaluate safety and efficacy compared to parallel design.5 parameters of testntone for short term and in small scale. 4. Reduce the bias as related to selection of 4. High chances of dropout of subjects during subjects in this study by allowing the study.5

randomization.5 5. Subjects with genetic variations will give 5. There are high risks arise with active drug in quality data.5 andropause which may led to adverse effect in subjects.6 6. Double blind avoid the bias related to the treatment to evaluate accurate result of active drug and testntone.

Preferred study design:

The more favorable study design is mentioned here to evaluate the safety and efficacy of the testntone in male andropause. Objective: To evaluate the effects of the testntone in comparison to active drug in male andropause. Main outcome measures: Primary outcome is improvement in andropausal symptoms. Secondary outcome is risks of prostate cancer, erythrocytosis and infertility. Design, setting, and participants: The randomized, double blind, active control, parallel study design will be conducting in multicenter. Enrolling the subjects will be male andropause, aged 50-65 years. Justification of study design: For this study block randomization become very effective than simple and stratified randomization process. Sometimes recruitment gap arise during the study, at that time block randomization becomes very useful. In block randomization subjects are divided into n number of blocks.5 Each block contains 4 subjects. The subjects in the block further divided into two subgroups. Group A (n=2) will receive testntone and group B (n=2) will receives active drug. This pattern will apply to each block. In this study the double blind is more appropriate rather than open label or single blind or triple blind. Subjects and investigator dont know which patient is to receive which treatment.5 It is useful to comply with study and to avoid bias related with treatment.5 Due to market competition it is mandatory to be evaluating the benefit-risk ratio of testntone. Benefit-risk ratio of testntone will be evaluated by comparing it with active drug (currently
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existing drug which is useful in andropause) and also to avoid ethical issues and political problems use of active-control group becomes very effective. There is some controversial risk (e.g. prostate cancer) with the use of standard available active drug in andropause.6 To evaluate controversial risk, it is mandatory to provide parallel design for testntone. It takes long time to evaluate the test drug. But it is more useful to evaluate the effects of testntone for long term use in the andropause. Conclusion: The justification of randomized, double blind, active control, parallel study design obligates to conclude it as more desired method to evaluate the safety and efficacy of new compound testntone for andropausal men.

References:
1. Li, C. I. et al. (2003), Relationship between long durations and different regimens of hormone therapy and risks of breast cancer, Journal of American Medical Association, Vol. 289, p. 3254-3263. 2. Million Women study collaborators. (2003), Breast cancer and hormone- replacement therapy in the million women study, The Lancet, Vol. 362, p. 419- 427. 3. The womens health initiative steering committee. (2004), Effects of conjugated equine estrogen in postmenopausal women with hysterectomy, Journal of American medical association, Vol. 291, No. 14, p. 1701- 1712. 4. Tripathi, K. D. (2003), Gonadal hormones (sex hormones) and their antagonists, in: Tripathi, M. , Essentials of medical pharmacology, Jaypee Brothers medical publishers (p) Ltd, New Delhi, p. 266-291.
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5. Spilker, B. (1991), Guide to clinical trials, Lippincott Williams & Wilkins, Philadelphia. 6. Rhodern, E. L. and Morgentaler, A. (2004), Risks of testosterone- replacement therapy and recommendations for monitoring, The new England journal of medicine, Vol. 350, p. 482- 492.

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