Androgen‐modulating agents for spinal bulbar muscular atrophy/Kennedy's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of androgen‐modulating agents for spinal bulbar muscular atrophy (also known as Kennedy's disease).
Background
Description of the condition
Spinal bulbar muscular atrophy (SBMA), also known as bulbospinal muscular atrophy or Kennedy’s disease, is an uncommon, X‐linked inherited, neurodegenerative disease (Banno 2012; Kennedy 1968). SBMA has an estimated prevalence of 1 to 2 per 100,000 men (Finsterer 2010; Guidetti 2001), and manifests clinically in men, whereas women carrying the gene usually do not exhibit any symptoms or signs. SBMA is characterised by degeneration of lower motor neurons of the brainstem and spinal cord, which results in progressive muscle weakness and atrophy of the bulbar, facial and limb muscles (Katsuno 2006; Tanaka 2012), ultimately leading to disability. Affected individuals may also manifest endocrinopathies, of which androgen insensitivity syndrome is the most prominent. Gynaecomastia is its most common clinical sign, followed by testicular atrophy, decreased libido and subfertility. In terms of hormonal profile, most affected men show partial androgen resistance with unusually high testosterone levels (Dejager 2002).
The endocrine and the nonspecific motor abnormalities such as postural tremor and muscle cramps often precede the onset of muscle weakness, which usually begins between 30 and 60 years of age (Atsuta 2006; Katsuno 2010b; Katsuno 2012; Rhodes 2009). The course of the disease is slow and insidious, and it may be decades before people with the condition need assistance to walk (Atsuta 2006). With optimal care and prevention of complications, such as aspiration pneumonia and falls, life expectancy may not be compromised (Finsterer 2010).
In terms of the molecular basis, the pivotal cause of SBMA is the pathological expansion of a trinucleotide cytosine‐adenine‐guanine (CAG) repeat in the androgen receptor (AR) gene, which gives rise to expansion of the polymorphic polyglutamine tract within the AR (La Spada 1991; Katsuno 2010b). People with SBMA have 38 to 62 CAG repeats within the AR gene, as opposed to the normal range of 9 to 36 (La Spada 1991; La Spada 2014; Tanaka 1996). Higher numbers of CAG repeats are associated with an earlier age of onset and greater disease severity (Adachi 2005). This polyglutamine‐expanded AR leads to toxic gain‐of‐function in the mutant AR protein, and disrupts normal function of the AR, causing neuronal dysfunction in people with SBMA (Katsuno 2012; Li 1998).
The clinical diagnosis of SBMA should be considered in men presenting with spinal and bulbar lower motor neuron disease symptoms, absence of upper motor neuron signs, androgen insensitivity signs and positive family history of X‐linked inheritance (La Spada 2014). The diagnosis can be confirmed on molecular genetic testing by detection of the trinucleotide CAG repeat expansion (La Spada 2014).
Description of the intervention
The androgen‐dependent nature of SBMA has been the main focus of SBMA research since the discovery of the mutant AR gene in 1991 (La Spada 1991). The evidence on androgen‐modulating therapeutic strategies, such as leuprorelin acetate and dutasteride, in reducing androgen levels has been encouraging (Katsuno 2003; Takeyama 2002). This therapeutic approach, also known as androgen deprivation, androgen ablation, androgen reduction, anti‐androgen or hormonal therapies, has recently been translated into clinical trials (Fernandez‐Rhodes 2011; Katsuno 2010a). Leuprorelin acetate, a synthetic non‐peptide gonadotrophin releasing hormone (GnRH) analogue, acts as an inhibitor of gonadotropin secretion, which in turn down‐regulates the secretion of testosterone from the testes and subsequently decreases the production of dihydrotestosterone (DHT), which is a more potent derivative of testosterone (Wilson 2007). The use of leuprorelin acetate is primarily indicated in the treatment of advanced hormone‐sensitive prostate carcinoma, endometriosis, and central precocity (Wilson 2007). Dutasteride, a dual inhibitor of 5α‐reductase that blocks conversion of testosterone to dihydrotestosterone (DHT), is used for benign prostatic hyperplasia and alopecia (Tindall 2008). There is currently no licensed pharmacotherapy for SBMA.
How the intervention might work
SBMA specifically affects males, as the activation of toxic effect on the mutant AR gene is closely related to androgen levels. The relationship between testosterone reduction and disease phenotypes has been well demonstrated in SBMA animal models. Castration not only prevented disease progression and deterioration, it also induced the reversal of phenotypic expression in male transgenic SBMA mice (Chevalier‐Larsen 2004; Katsuno 2002; Katsuno 2003; Yu 2006). On the other hand, testosterone administration accentuated the neuromuscular disease phenotype in female transgenic mice (Katsuno 2002).
Androgen‐modulating agents such as leuprorelin acetate and dutasteride might prevent the toxicity of the polyglutamine‐expanded AR by reducing serum androgen levels. A potent gonadotrophin inhibitor, leuprorelin acetate, has been shown to bring about a significant improvement in the neuromuscular phenotypes by suppressing the nuclear accumulation of mutant AR in transgenic SBMA mice (Katsuno 2003). Dutasteride blocks the activity of 5α‐reductase for the conversion of testosterone to DHT (Parodi 2011; Poletti 2004). In SBMA animal models, 5α‐reductase was found highly expressed in skeletal muscle and motor neurons (Pozzi 2003; Sar 1977; Thigpen 1993); the abundance of DHT induces the expression of mutant AR and causes neurodegeneration (Takeyama 2002). Dutasteride provides a targeted anti‐androgen strategy and, therefore, the normal anabolic effect of testosterone in muscle is preserved. Studies on the treatment of SBMA patients with androgen‐modulating therapy have not shown a significant effect on the progression of muscle weakness or swallowing function (Fernandez‐Rhodes 2011; Katsuno 2010a). Treatment was well tolerated but potential effects of androgen‐modulating therapies include erectile dysfunction, decreased libido, fatigue and osteoporosis, which may affect the quality of life of these men (Higano 2003; Roehrborn 2008).
Why it is important to do this review
SBMA, like most of the neurodegenerative diseases, has long been considered as incurable. Current treatment options of SBMA merely focus on alleviation of symptoms and maintaining optimal functional status. The efficacy of androgen‐modulating therapy in SBMA has not undergone systematic review. With current advances in molecular technologies, a meta‐analysis of the usefulness of androgen‐modulating therapy is necessary to inform the direction of future research. Furthermore, a systematic review examining both clinical outcomes and adverse effects is needed because androgen‐modulating therapy may ameliorate the neurological manifestations but accentuate the troublesome symptoms related to androgen insensitivity.
Objectives
To assess the effects of androgen‐modulating agents for spinal bulbar muscular atrophy (also known as Kennedy's disease).
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) and quasi‐RCTs. We will include studies reported as full text, those published as abstract only, and unpublished data. There will be no restrictions as to language. Quasi‐RCTs are studies in which participants are allocated to groups by methods that are partly systematic, for example by date of birth, case record number or alternation.
Types of participants
We will include all males with spinal bulbar muscular atrophy (SBMA) and at least one relevant neurological symptom or sign, such as muscle weakness, muscle wasting, or bulbar palsy. The diagnosis of SBMA is confirmed by genetic analysis with detection of androgen receptor CAG repeat expansion of more than 38 repeats (La Spada 2014).
Types of interventions
We will include any androgen‐modulating agent compared to a placebo, an alternative treatment or no treatment.
Types of outcome measures
Primary outcomes
-
Change in performance testing at 12 months, and if available at 24 months, measured by the 6‐minute walk test.
Secondary outcomes
-
Change in swallowing function at 12 months, and if available at 24 months, measured by pharyngeal barium residue and cricopharyngeal opening duration (quantitative measurement in videofluorography).
-
Change in muscle strength at 12 months, and if available at 24 months, measured by maximum voluntary isometric contraction.
-
Change in lung function at 12 months, and if available at 24 months, measured by lung function values (forced expiratory volume in one second/forced vital capacity (FEV1/FVC) and vital capacity as the percentage of predicted (%VC)).
-
Change in quality of life at 12 months, and if available at 24 months, measured by amyotrophic lateral sclerosis assessment questionnaire 5 (ALSAQ‐5) (Jenkinson 2000).
-
Change in glucose tolerance at 12 months, and if available at 24 months, measured by glycosylated haemoglobin (HbA1c).
-
Adverse events: all adverse events, including gynaecomastia, loss of libido, impotence, erectile dysfunction, and osteoporosis; severe or serious adverse events that lead to hospitalisation or death; and adverse events leading to cessation of treatment.
Search methods for identification of studies
Electronic searches
The Trials Search Co‐ordinator will search the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, current issue in The Cochrane Library), MEDLINE (January 1966 to current), and EMBASE (January 1980 to current). The draft MEDLINE search strategy is in Appendix 1.
We will also conduct a search of the United States (US) National Institutes for Health Clinical Trials Registry, ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organisation (WHO) International Clinical Trials Registry Portal (ICTRP) (apps.who.int/trialsearch/) for ongoing or completed but unpublished studies. We will search all databases from their inception to the present, and we will impose no restriction on language of publication.
Searching other resources
We will search reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for trial information.
Data collection and analysis
Selection of studies
Two review authors (HB and SJ) will independently screen titles and abstracts of all the studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports or publications and two review authors (MS and WA) will independently screen the full text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (HZ). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a 'Characteristics of excluded studies' table and PRISMA flow diagram (PRISMA 2009).
Data extraction and management
We will use a data extraction form for study characteristics and outcome data, which has been piloted on at least one study in the review. One review author (MS) will extract the following study characteristics from included studies.
-
Methods: study design, total duration of study, details of any 'run in' period (period before treatment begins), number of study centres and location, study setting, withdrawals, and date of study.
-
Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline characteristics, inclusion criteria, and exclusion criteria.
-
Interventions: intervention, comparison, concomitant medications, and excluded medications.
-
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
-
Notes: data on missing data, loss to follow‐up, attrition, funding for trial, and notable conflicts of interest of trial authors.
Two review authors (FK and WA) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if the paper does not report outcome data in a usable way. We will resolve disagreements by consensus or by involving a third person (HZ). One review author (HB) will transfer data into Review Manager (RevMan 2014). A second review author (MS) will check the outcome data entries and assess study characteristics for accuracy against the trial report.
When reports require translation, the review authors will extract data from the translation provided. Where possible a review author will check numerical data in the translation against the study report.
Assessment of risk of bias in included studies
Two review authors (MS and HB) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (SJ). We will assess the risk of bias according to the following domains.
-
Random sequence generation.
-
Allocation concealment.
-
Blinding of participants and personnel.
-
Blinding of outcome assessment.
-
Incomplete outcome data.
-
Selective outcome reporting.
-
Other bias.
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
As most of the outcome measures are continuous outcomes, we will use mean differences (MDs), or standardised mean differences (SMDs) for results across studies with outcomes that are conceptually the same but measured in different ways.
For most of the outcome measures, we will calculate the rates of progression for participants on androgen‐modulating agents for spinal bulbar muscular atrophy versus those on placebo or other comparison treatment.
We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will narratively describe skewed data reported as medians and interquartile ranges.
Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting.
Unit of analysis issues
The unit of analysis will be the individually recruited participant, which is usually also the unit of randomisation in the type of trials that we will take into account. We will consider the level at which randomisation occurred that may be different, such as in cross‐over trials and cluster‐randomised trials. In cross‐over trials, we will use generic inverse variance (GIV) to analyse the results once differences in effects and standard errors have been estimated.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is available as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial unexplained heterogeneity we will report it and explore possible causes by prespecified subgroup analysis.
Assessment of reporting biases
We anticipate that it is unlikely that there will be sufficient studies to assess small study effects using a funnel plot, as this is a rare condition and a minimum of 10 trials is recommended for such an assessment (Sterne 2013).
Data synthesis
We will perform data synthesis and data analysis using the latest version of the Cochrane Review Manager software. We will follow the statistical guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use a fixed‐effect model unless there is evidence of substantial statistical heterogeneity. The results from both fixed‐effect and random‐effects analyses will be presented. If the review includes more than one comparison that cannot be included in the same analysis we will report the results for each comparison separately.
'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes: performance testing, swallowing function, muscle strength, lung function, quality of life, glucose tolerance and adverse events. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We will analyse subgroups of studies categorised according to duration of treatment (12 months' duration versus 24 months' duration) if data are available.
Sensitivity analysis
We plan to carry out the following sensitivity analyses:
-
Repeat the analysis excluding unpublished studies (if there were any).
-
Repeat the analysis excluding studies at high risk of bias.
-
If there is one or more very large study, repeat the analysis excluding large studies to look at how much they dominate the results.
