The suitability of polycystic ovary syndrome-specific questionnaires for measuring the impact of PCOS on quality of life in clinical trials

Objectives: Generic patient-reported outcome (PRO) measures underestimate the impact of polycystic ovary syndrome (PCOS) on quality of life (QoL). The aim of this review was to identify PCOS-specific QoL measures and establish whether their development history and measurement properties support their use in clinical trials.

Methods: A systematic search was conducted using terms synonymous with “PCOS” and “QoL.” Following identification of measures, further searches were undertaken using the questionnaire name and abbreviation to explore its use, development history, and demonstrated measurement properties.

Results: Of 56 abstracts screened, 21 reported using PRO measures. One PCOS-specific QoL measure was identified: the PolyCystic Ovary Syndrome Questionnaire (PCOSQ). Nine papers show that the PCOSQ’s development history is somewhat incomplete, and that it does not have good content validity. The PCOSQ subscales demonstrate acceptable levels of reliability (0.70–0.97) and partial known-groups validity as well as convergent/divergent validity with other PRO instruments. Responsiveness
to change is variable and minimally important differences have not been established.

Conclusions: The PCOSQ is the only condition-specific measure of the impact of PCOS on QoL. Additional research is required to ensure its comprehensiveness, sensitivity, and to guide interpretation prior to including in clinical trials.

Patient use of smartphones to communicate subjective data in clinical trials

Purpose. Various methods have been used in clinical trials to collect time-sensitive subjective responses, including study diaries, telephone interviews, and use of text messaging. However, all of these methods are limited by the uncertainty of when the participants enrolled in the study actually record their responses. This technical note reports on the utility of the BlackBerry smartphone to collect such data and why such a system provides advantages over other methods to report subjective ratings in clinical studies.

Methods. The Centre for Contact Lens Research developed an on-line web-enabled system that permits participants to record and immediately transmit subjective rating scores in numerical form directly into a web-enabled database. This, combined with the utility of BlackBerrys, enabled time-specific e-mail requests to be sent to the study participants and then for that data to be simultaneously transmitted to the web-enabled database. This system has been used in several clinical trials conducted at the Centre for Contact Lens Research, in which data were collected at various times and in several specific locations or environments.

Results. In the clinical trials conducted using this system, participants provided responses on 97.5% of occasions to the requests for data generated by the automated system. When the request was for data on a set date, this method resulted in responses of 84.1% of the time.

Conclusions. The series of clinical trials reported here show the benefits of the utilization of the BlackBerry to collect time- or environment-sensitive data via a web-enabled system.

Zinc for treating of children and adolescents with attention-deficit hyperactivity disorder : a systematic review of randomized controlled clinical trials

This study systematically reviews the randomized clinical trials examining the effect of zinc on attention-deficit hyperactivity disorder (ADHD), searching the PubMed/Medline and Scholar Google databases. All randomized controlled trials that examined zinc as the intervention, and ADHD as the primary outcome were included. Only three randomized controlled trials, one which included a community sample and two that included clinical samples, met inclusion criteria. The only trial that was well controlled and randomized according to the baseline zinc level showed that using zinc, either alone or in combination with stimulants, did not improve ADHD. Considering the lack of clear evidence for the effect of zinc on ADHD and the possible effect of zinc on the nervous system, more clinical studies are needed to prove or disprove the effect of zinc as a monotherapy or adjuvant therapy.

A new framework for interpreting the outcomes of imperfectly blinded controlled clinical trials

It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient's expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.

Assessing blinding in clinical trials

The interaction between the patient's expected outcome of an intervention and the inherent effects of that intervention can have extraordinary effects. Thus in clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind it. Yet, in practice perfect blinding is impossible to ensure or even verify. The current standard is follow up the trial with an auxiliary questionnaire, which allows trial participants to express their belief concerning the assigned intervention and which is used to compute a measure of the extent of blinding in the trial. If the estimated extent of blinding exceeds a threshold the trial is deemed sufficiently blinded; otherwise, the trial is deemed to have failed. In this paper we make several important contributions. Firstly, we identify a series of fundamental problems of the aforesaid practice and discuss them in context of the most commonly used blinding measures. Secondly, motivated by the highlighted problems, we formulate a novel method for handling imperfectly blinded trials. We too adopt a post-trial feedback questionnaire but interpret the collected data using an original approach, fundamentally different from those previously proposed. Unlike previous approaches, ours is void of any ad hoc free parameters, is robust to small changes in auxiliary data and is not predicated on any strong assumptions used to interpret participants' feedback.

Application of the gradient boosted method in randomised clinical trials: participant variables that contribute to depression treatment efficacy of duloxetine, SSRIs or placebo

Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes.

Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review

N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.

Nucleic acid-based aptamers: applications, development and clinical trials

Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.

Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

The use of mixed methods in drug discovery: integrating qualitative methods into clinical trials

Contemporary methods in clinical trials are pivoted around hypothesis confirmation, not generation. This is a problem for new drug discovery, since the pharmacokinetic or receptor profile of most novel agents do not link to pathophysiology, which is very poorly understood. Therefore, it is difficult to impute the therapeutic potential of a candidate agent. Most psychotropic agents were discovered serendipitously, either through careful clinical observation or by researchers finding unexpected associations in datasets. Methods that increase the ability to detect latent signals in data are needed. These include mixed methods that incorporate qualitative methods into randomized controlled trials.

This chapter proposes a methodology for the integration of mixed methods in clinical trials, fusing qualitative and quantitative methods, and presents an exemplar using this approach.

Mixed methods show potential for signal detection, hypothesis generation, and associations that may be otherwise undetected in traditional clinical trials.