Trial Management

Background: Insomnia is a sleep disorder that is characterized by dysfunctional sleeping patterns. This entails inability to initiate and maintain sleep and inability to resume sleeping. These symptoms are exhibited by a patient who has the opportunity to sleep comfortably. Various studies have investigated the use of melatonin, a neurohormone to treat insomnia although no ample evidence has been realized thus far.

Objective: The principle objectives of the clinical trial are to investigate the effect of melatonin in enhancing and maintaining sleep in insomniacs. Secondly, to investigate the effects of melatonin in reverting non-restorative sleep in insomniacs. Lastly, to investigate the effect of melatonin in relieving the adverse effects of insomnia.

Methods: This crossover design double-blind study will investigate the role of melatonin in treating insomnia in patients between 18-60 years old. The study will be carried out at two referral hospitals, Brooklyn University Hospital and Mount Sinai Hospital. The study will involve a total of 60 patients and the trial will take one year. Each patient will receive doses of the test treatment (melatonin) and placebo. Cognitive tests, psychomotor tests and sleep questionnaires will also be administered. The data will be analyzed using the Grizzle model and sub-group analysis will be carried out using the Z- statistic test.

The state recognized as sleep disorder occurs when an individual suffers from poor quality sleep ultimately resulting in excessive sleepiness, impaired functioning and lack of sleep(insomnia). The latter is a condition that literally means the inability of one to sleep. The term insomnia is also widely used to describe cases in which polysomnographic evidence is present with regard to disturbed sleep.  Hence prolonged periods of sleep latency or wakefulness, repeated nocturnal wakenings as well as recurrent transient arousals are all signs of insomnia. Insomnia is viewed as both a sign and symptom of disease (Buscemi et al., 2004). However, for the purpose of this study, insomnia is a disorder on the basis of the following clinical diagnostic criteria. First, difficulty sleeping, remaining asleep or inability to resume sleeping. Secondly the difficulty is prevalent despite prevailing opportunities to sleep. Third, this state of dysfunctional sleeping patterns is linked to distress or daytime impairment. The fourth diagnostic symptom is the persistence of the sleeping problem at least thrice a week for a period no shorter than one month. Insomnia qualifies consideration as a disorder as it’s a condition with negative sleeping patterns. Most important, these conditions are abnormal results and point to a pathological response. This is because the results of insomnia are different from the normal effects of ordinary sleep loss.  According to population based studies, approximately 30% of adult samples across different countries report at least one symptom of insomnia. These includes: poor quality/nonrestorative sleep, difficulty maintaining and/or initiating sleep (Roth, 2007).

Intervention Description(Melatonin)

Melatonin is a hormone and in full is N-acetyl-5-methoxytryptamine. It is secreted by the pineal, located at the brain’s third ventricle. The  main precursor is the amino acid tryptophan which is hydoxylated to  form intermediate  5-hydroxytryptophan. The latter is subsequently decarboxylated to form 5-hydroxytryptamine, commonly known as serotonin. Serotonin is converted to N-acetylserotonin by the N-acetyltransferase enzyme.  The latter is methylated to produce melatonin by hydroxyindole-o-methyltransferase  enzyme.  Melatonin is legalized for sale as a pharmaceutical drug. It is isolated from the bovine pineal gland in cattle. On a commercial scale, it’s mainly chemically synthesized from the compound, 5-methoxytryptamine (Vohra and Klassen, 2004).

Justification of the Trial

Insomnia is a chronic disorder and there is need to investigate an effective remedy.  Melatonin holds great potential in curing insomnia. Insomnia has reduced the quality of life  and led to poor physical functioning, physical and mental health problems, bodily pain, low vitality, poor social functioning for patients. In a study by Wurtman and colleagues, melatonin was proven to help old adult insomniacs to sleep well. "According to our research, the physiological dose of melatonin of about 0.3 milligrams restores sleep in adults over the age of 50. The adults who would normally wake up during the second and third thirds of the night were able to sleep through the night with the 0.3 milligram dosage."(Halber,  2001). However these results cannot be extrapolated for the general population that comprises of children and young adults.  Other studies have yielded inconclusive evidence concerning the effect of melatonin on sleep.  A firm conclusion cannot be drawn on melatonin effectiveness on alleviating insomnia. This mainly due to heterogeneity and confounding variables in individuals with secondary and primary sleep disorders. Melatonin has not been proven effective for the relieve of sleep disturbances linked to shift-work disorder and jet lag. However there is evidence, on the use of melatonin in easing the treatment of delayed sleep phase syndrome (Wilan  and Pater, 1996).

Previous clinical trials on the efficacy of melatonin in treating insomnia have been case control studies. Comparisons have been made with the experimental group in which melatonin was administered and a control group that receives the placebo. A randomized crossover design would be appropriate in assessing the efficacy of melatonin on individuals. This will eliminate

the case of between-subject variability. The effect will be conclusive when melatonin is found effective on subjects as compared to the placebo administered on the same individual.

Hypothesis (Ho)

Melatonin has no effect in treating insomnia.

Principle Objectives

1. To investigate the effect of melatonin in enhancing and maintaining sleep in insomniacs.

2. To investigate the effect of melatonin in reverting non-restorative sleeps in insomniacs.

3. To investigate the effect of melatonin in relieving the adverse effects of insomnia.

Material and Methods

Eligibility

Ages Eligible for Study:   18-60

Genders Eligible for Study:   Both

Accepts Healthy Volunteers:   No

Inclusion Criteria:

• Low level of endogenous melatonin
• Evidence of insomnia upon assessment

Exclusion Criteria:

• Asthma
• Liver disease
• Cancer- leukemia, lymphoma etc.
• Dementia
• Current substance abuse- alcohol, nicotine and opiates
• Restless leg syndrome
• Sleep apnea

Ethical Considerations

Ethical clearance and authorization will be obtained from the relevant Ethics Committee. All participants will be recruited upon obtaining a prior and informed consent and each subject will fill a consent form. The subjects will be duly informed on the purpose of the study. They will also be informed on the experimental doses that shall be administered in the study. In addition, subjects will be informed on any potentially adverse effects that might arise after administration of any treatment.

Trial Design

The randomized control trial will assume a crossover design. Two treatments will be administered i.e. melatonin and the placebo. The subjects will be assigned to two arms in the study. The participants will be randomly assigned to the arms after blocking on the basis of age to ensure that all ages from 18 to 60 are represented in each arm. The first treatment (placebo or melatonin) will be used for the first period which will comprise of 6 months. After a wash out period of 2 months, the subjects will be switched to the alternative second treatment (placebo or melatonin).

Subjects will be required to make a sleep diary before the administration of either treatment to last throughout the trial. Polysomnograph machines will be attached to patients as they will aid in measuring sleep efficiency. The test group will sequentially receive a low dose (0.4 mg), moderate dose (2.0 mg) and high dose (4.0 mg) of melatonin. Adverse effects will be monitored in the patients.  Cognitive tests, psychomotor tests and sleep questionnaires will also be administered. This will be used to assess participants throughout the study. Subjects will also be reassessed for two months as a form of follow-up after the study ends to check for adverse effects.

Methods for Protecting against Bias

1.Randomization

Randomization will be the first strategy to protect against bias. Participants will be randomly assigned to either of the two arms in the study. Secondly each group will have members from all ages from 18 to 60. Thus each group will have the same age sets. The effect of melatonin will be evaluated for both adults and the elderly in each group.  Hence the findings will be generalized for the target population.  The proposed study groups will be located in two institutions. One group will be in Manhattan and the second group will be in Brookyln. This separation will eliminate bias and results from the two groups will be independent.

2. Blinding

Blinding will also be carried out to eliminate bias. Specifically, the study will be a double blind trial in which case both the subjects and the researchers will not be aware of the nature of the treatment (placebo or test). This will be achieved by using a matching placebo similar in appearance and even smell to the test treatment (melatonin). The subjects will report objective results as they will not be influenced by the knowledge of treatment received. The research assistants will also make objective measurements as they will not be influenced by knowledge of treatment administered.

Proposed Outcome Measures (Wilan and Pater, 1996).

Primary Outcome:

• Sleep efficiency (objective and subjective)
• Neurobehavior assessment battery

Secondary Outcome Measures:

• Psychomotor  testing
• Evaluating sleepiness questionnaire.

Sample Size

The crossover study being a small scale study will have a power β of 95%. The chosen level of significance α will be 5% with a P of 0.05.  The standard deviation of the crossover design will be expressed as a within patient standard deviation. This refers to the standard deviation of   recurrent observations made on an individual. A sample size n of 30 was achieved after using the formula (Kirby et al., 2002).

1 − β = T _n-1 (tα/2,n−1)

Recruitment of Participants

Participants will be recruited after clearance and authorization is granted by the Ethics Committee. The target sample size is 60 participants as each arm will have 30 participants. Using the inclusion criteria, subjects with insomnia will be recruited and consent obtained 2 months before the study commences. Subjects will be dismissed on the basis of conditions stated in the exclusion criteria.  The subjects will be recruited in New York and randomly assigned to the two centers i.e. Manhattan and Brooklyn.

Randomization Technique: Stratified Randomization by blocking

We will generate a randomization schedule, consisting of a block of four numbers. In this two-armed trial this produces the following allocations: ABAB; AABB; BABA; BBAA; ABBA; BAAB. A block of four allocations will be randomly selected from the six possible sets of blocks. The next block will be selected randomly, until the point at which all possible participants can be randomized through the string of blocks. Selection for treatment groups will be determined by a computer generated randomization list in a 1:1 ratio (PRM mg to placebo). The list will be constructed using the method of randomized permuted blocks. Randomization will be stratified by trial site, 6-SMTlevels (low/high) and age group (< 65/> 65). In order to achieve a balance in participants in our two arm trial, we will produce a random list of numbers and assign participants in the control group with even numbers and participants in the intervention group, odd numbers.  This procedure will be performed for all participants using the centralized IVRS randomization system. This will keep both the research personnel (nurses and investigator) blind to the study treatments

The patients might not faithfully make records of sleeping patterns on the sleep diaries.  It is for this reason, close monitoring will be undertaken. However useful data will be collected from neurobehavior assessment, psychomotor testing and evaluation of sleepiness questionnaires.  The patients will be counseled to remove feelings of pessimism on drug success as this might prevent consistent consumption of the drug.  The treatments will also be packaged in small capsules to ensure participant comfort.  In the course of counseling, subjects will be encouraged to have the right and not very high expectations of the therapeutic intervention.  Most important a good working relationship will be established with patients to avoid study drop-outs.

Data Analysis

The  Grizzle model will be adopted for data analysis.  This model will determine if there will be a significant difference between the effect of the test treatment (melatonin) and that of the placebo.

Y_ijk  =  µ + b_ij + _k + _m + _m + _ijk

 b_ij  = effect of j^th patient within i^th sequence

_k = effect of k^th period

_m =direct effect of m^th drug

_m = residual effect of m^th drug

_ijk  = random error

Estimation of carry-over Effects

₁-( %u0176 _1.1+ %u0176 _2.1) – (%u0176 _1.2 + %u0176 _2.2)

            AB seq                 BA seq

Estimation of Treatment Effects

Φ₁ – %u03D5 ₂ = %u0176 _1.1 – %u0176 _1.2

Using first period data

Φ₁ – %u03D5 ₂ ={ (%u0176 _1.1 – %u0176_2.1 ) - (%u0176 _1.2 – %u0176_2.2 ) }/2

Assuming  %u019B ₁ = %u019B ₂

Overall where (sequence, patient, period)

Subgroup Analysis

4(K) Interim analysis will be carried out in each group. Hence the study is going to be divided into K hence 4 intervals. After each stage, the data will be accumulated for n=N/K patients. The interim analysis is going to be undertaken using Z statistic (Z_i ). The trial will only continue if

The following is fulfilled,

| Z_i| ≤ z_i i=1,….K-1,

Otherwise the trial will be terminated and the null hypothesis will be rejected. The trial can also be terminated after the final interim analysis. This will prove that the data will provide sufficient evidence to reject the null hypothesis. Hence there will be a significant difference between the placebo and test treatment (melatonin).

Economic Issues to be addressed

The quality of life of the respondents will be assessed. The will take into consideration the socioeconomic status of the respondents. Stress arising from hardship and poverty might trigger insomnia. Stressed patients might not have good quality sleep as a result of anxiety. Moreover stress is known to trigger hormonal imbalance and stressed patients might have low levels of endogenous melatonin.

Trial Management

-Ethical considerations will be taken into account with regard to trial authorization, the course of recruitment and handling of participants throughout the study.

-Randomization and double blinding will be employed to eliminate bias.

-Validated methodology will be used as stipulated in the protocol.

-Data entry will be carried out as soon as data is collected in appropriate tables and graphs will be utilized to show trends.

-Appropriate data abstraction procedures will be utilized in case of patient drop out.

-The subjects will be closely monitored and assisted to adhere to the protocol especially with regard to consistent consumption of test treatment and recording of results.

-Time management to ensure patients are enrolled on time and all activities are carried out in accordance to the stipulated timeline.

Attrition Rate

The expected drop –out rate in the participants is approximately 20%. Participants might withdraw due to waiver of consent. Others might withdraw for personal reasons and possible adverse effects from treatment.

Trial Centers

The clinical trial will involve two centers:

1. Mt. Sinai Hospital, Manhattan. It is a teaching referral hospital and has a high bed capacity of 1,171.

2. University Hospital of Brooklyn. It is a teaching referral hospital.

Patients will be monitored from the two centers as treatments are administered.

Budget and Justification of Resources