Interventions for ulceration and other skin changes caused by nerve damage in leprosy

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of self-care, dressings, and footwear in preventing and healing secondary damage to the skin in persons affected by leprosy.

Background

We have included a glossary with an explanation of some of the terms we have used, see Table 1.

Table 1. Glossary of terms
TermDefinition
Afferent nervesSensory nerves that carry information from the outside world, such as sensations of heat, cold, and pain, to the brain and spinal cord.
Autonomic fibresNerve fibres that collectively make up the sympathetic (involuntary) and parasympathetic ("relaxation response") parts of the autonomic peripheral nervous system. Common symptoms of autonomic nerve damage include an inability to sweat normally and change in vasodilatation.
BacilliPlural of bacillus, bacteria.
Capillary haemodynamicsBlood flow in the capillaries, where oxygen transfer occurs in the body.
Efferent nervesMotor nerves that transmit impulses from the brain and spinal cord to the muscles.
Facial nerveIt is composed of motor, sensory fibres and autonomic fibres. The important motor part innervates the facial muscles responsible for eye closure and mouth and facial movements. In leprosy, the eye is at risk of corneal ulceration for exposure and decreased lachrymal gland function.
FibroblastA large flat cell that secretes the proteins that form collagen and elastic fibres and the substance between the cells of connective tissue.
Medial nerveIt is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the lateral side of the forearm and the palmar side of the hand, thumb, index, middle, and half of the ring finger. It innervates the muscles of the hand and in leprosy affects predominately the intrinsic muscles of the thumb making opposition and prehension difficult. Weakness and paralysis causes the thumb to be flat within the hand.
Motor fibresMotor nerves, or efferent nerves, transmit impulses from the brain and spinal cord to the muscles.
MultibacillaryHaving numerous bacilli. "Multibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with more than five lesions.
PaucibacillaryHaving just a few bacilli. "Paucibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with five or fewer lesions.
Peripheral nerveA vast transmission network of afferent and efferent nerves from the central nervous system (brain and spinal cord) distally to every other part of the body. The motor, sensory, and autonomic fibres have specific functions within the area innervated by the specific peripheral nerve. Nerves can be composed primarily of motor or sensory fibres or be mixed, having both motor and sensory fibres.
Peroneal nerveThe common peroneal divides into the superficial and deep peroneal branches. The deep branch innervates the muscles of the anterior compartment of the leg (anterior tibial muscle, the long extensor muscle of the big toe and the long extensor muscles of the toes). When weak or paralysed, it makes it difficult to lift the foot and toes as well as evert the foot when walking. In leprosy, it is frequently referred to as "foot drop". Its sensory fibres innervate the lateral dorsal surface of the lower leg and foot. The sensory fibres of the superficial branch provides sensation to the web space of the big toe and the medial surface of the second toe.
Tibial nerveOne of the two major divisions of the sciatic nerve, it courses down the back of the leg to terminate as the medial and lateral plantar nerves in the foot; it supplies the hamstring muscles, the muscles of the back of the lower leg, and the intrinsic muscles of the foot. It causes clawing of the toes if muscles are paralysed. It provides sensation to the back of the leg and sole of the foot. The sensory loss to the sole of the foot puts the foot at high risk for injury and ulceration.
Sensory fibresSensory nerves, sometimes called afferent nerves, carry information from the outside world, such as sensations of temperature (hot, cold), touch, texture and pain, to the brain and spinal cord. They alert the body to pleasant feelings as well as to danger.
Sural nerveA sensory nerve in the calf region (sura) of the leg. It is made up of collateral branches of the tibial nerve and common fibular nerve.
Trigeminal nerveThe three-branch trigeminal (fifth cranial) nerve innervating the face, eyes, nose, mouth, and jaws. The corneal sensory loss in leprosy can cause the eye to be at risk for increased dryness and corneal abrasions.
UlcerationFormation or development of an ulcer. On the skin, it is a loss of epidermis, often part of the dermis and even subcutaneous fat layers of the skin.
Ulnar nerve in the upper extremityIt is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the ulnar (medial) side of the forearm, hand, the palmar side of the 5th and half of the 4th fingers. It innervates the muscles of the hand and in leprosy affects predominately the distal intrinsic muscles used for fine motor tasks. Weakness and paralysis causes finger clawing.
VasodilationA widening of the blood vessels caused by a relaxation of the smooth muscle cells in the vessel wall. The sympathetic nervous system has nerves that play an important role in vasodilatation and vasoconstriction.

Description of the condition

Leprosy (Hansen's disease) is a chronic infectious disease caused by the bacterium Mycobacterium leprae (M. leprae) (Lockwood 2002). Official figures show that almost 189,000 people, mainly in Asia and Africa, were affected at the beginning of 2013, with approximately 232,000 new cases reported during 2012, which is 6231 more cases than in 2011 (WHO 2013). The World Health Organization (WHO) stated in 2012 that less than 20 countries reported more than 1000 new cases, which indicates that leprosy is gradually becoming limited to a small number of countries (WHO 2012).

Although the incidence rate is declining slowly worldwide, it is rising in a few places. The proportion of children under 15 years of age among new cases of leprosy ranges widely in different countries: from 0.6% to 41.3% in 2012 (WHO 2012). Person-to-person transmission remains a problem; there are significant numbers of childhood cases, and many people suffer from the consequences of leprosy (McDougall 2002). Numbers are based on the people registered for treatment. Over 14,000 new cases of leprosy in 2012 were diagnosed with grade 2 disability (impairment of the eyes, hands, or feet), which is 0.25 per 100,000 population (WHO 2013), and in this report the proportion of new cases found with grade 2 disabilities ranged from 4.4% to 25.4%. This variation can be explained by the methods of detection and reporting in those countries: where there are low levels of grade 2 disabilities this indicates an increasing awareness of detecting cases early in communities and health systems. A total of 3427 relapses were reported from 105 countries in 2012 (WHO 2013).

South East Asia has the highest prevalence of leprosy, followed by the Americas, Africa, the Western Pacific, Eastern Mediterranean and Europe. Of all those identified as having the disease, 58% live in India, 16% live in Brazil, and 9% live in Indonesia (WHO 2012).

Chemotherapy with a combination of immunosuppressive and antibiotic drugs (multidrug therapy (MDT)) is used to treat leprosy (Lockwood 2002). The drugs used in MDT are rifampicin, dapsone, and clofazimine; they are effective in killing bacilli, but do not prevent further nerve damage. This nerve damage is caused by immune system responses, requiring other interventions such as corticosteroids, surgery, or both (Lockwood 2002). The effectiveness of corticosteroids has been evaluated in a systematic review (Van Veen 2007). Surgery for treating nerve damage in leprosy has been covered in another systematic review (Van Veen 2012). Virtually all people affected by leprosy and registered with their local health services are treated with MDT (WHO 2013). People affected by leprosy who are or have been treated with MDT are not infectious (WHO 2010).

Clinical manifestations and complications

Generally, leprosy starts with a patch or lesion on the skin, but it can also do damage to the nerves (Bell 1995; Lockwood 2002). Often the first signs are a lighter colour patch of skin with loss of hair, or sweating, or a loss of sensation to temperature and touch. If treated early, much of the nerve damage leading to problems in the face, hands, and feet can be prevented (Van Veen 2009). The principal manifestations are skin patches or lesions with a loss of sensation (flat or raised patches on the skin). Sometimes, there are only one or a few lesions, and sometimes there are numerous lesions, depending on host immunity. In those with a large number of bacteria, the skin may become diffusely thickened. Thickened skin; dry or cracked skin; or skin ulcers and peripheral neuropathy (inflammation of nerves) in the limbs damaging nerve function (autonomic, sensory, and motor fibres) may be later complications (Bell 1995; Lockwood 2002). Most complications are the result of nerve damage through direct invasion by the M. leprae bacteria or inflammation caused by reactions of the host's immune system.

Initially, the small sensory and autonomic nerve fibres in the skin are damaged, causing local loss of hair, sweating, and sensation and loss of the skin's ability to sweat. Damage to peripheral nerves eventually leads to more widespread skin dryness, loss of sensation, and weakness or paralysis of muscles in areas of the body supplied by the affected nerve. The eyes, hands, and feet, with loss of sensation, paralysis and dryness, are at a higher risk of injury. The dry skin can lead to cracks. If cracks, injuries, and ulcerations are not cared for and rested, they can become infected and lead to further injury and destruction, resulting in visible damage and destruction of the eyes, hands, and feet. These are easily seen impairments; this destruction and paralysis are visible and commonly known as grade 2 disability in leprosy (Lockwood 2002). If a new leprosy case is seen with a visible grade 2 disability (WHO 2013), then the diagnosis has been late. Community health education programs, health systems, or both, need to explore strategies to improve early case detection.

The primary peripheral nerves damaged by leprosy are the ulnar nerve in the arm, the peroneal and posterior tibial or sural nerves in the leg, and the trigeminal and facial nerves of the face. Major areas affected by nerve damage in leprosy are the hands (especially the palms), feet (especially the soles), and eyes (Lockwood 2002). The main complication of sensory nerve damage is ulceration followed by sensory loss, particularly of the feet (Lockwood 2002). The multidrug therapy offered to people infected with M. leprae is efficacious in killing the bacilli if given for a sufficient length of time of 6 to 12 months (WHO 2006). However, even with treatment, some people with leprosy can have immune reactions during and after treatment, which require immediate action to reduce the inflammation to prevent or minimise permanent secondary damage to skin and peripheral nerves. If the reaction is not identified and treated adequately, damage cannot be reversed (Lockwood 2002; Van Veen 2009).

Late diagnosis is the greatest cause of disability, followed by reactions that happen before, during, and after treatment. Frequently, they are either not identified, not treated adequately, or both. For those having permanent nerve damage, further damage and complications can be reduced by good self-care practices, the use of protective footwear, surgery, etc (Lockwood 2002). Existing guidelines (WHO 2011) emphasise the importance of preventing disabilities and mention "identify", "train", "support" and "integrate" as being important principles. Some strategies are suggested: (WHO 2011, page 11):

  • "Involve persons affected by leprosy to encourage individuals to go for early evaluation;

  • Formally engage persons affected by leprosy in the promotion of self-care and the identification of people in need of practising self-care;

  • Involve persons affected by leprosy in identifying individuals in need of aids and appliances such as protective footwear."

Successful rehabilitation is an important issue that can be achieved through a combination of efforts made by the community and the individuals with their families (WHO 2011).

Diagnosis

Leprosy is diagnosed clinically by three principal signs (Lockwood 2002):

  • skin lesions with a decrease in sensation, i.e., parts of the skin may feel numb and not able to detect temperature, touch, or painful stimuli such as a pin prick;

  • thickened peripheral nerves that can easily be felt through the skin; and

  • a positive smear, i.e., evidence of the causative bacterium, M. leprae, using microscopic examination of a sample of tissue (skin smear).

Classification

There are two main forms of classification (Lockwood 2002a). They are the Ridley-Jopling scheme and the World Health Organization (WHO) paucibacillary/multi bacillary (PB/MB) classification.

Ridley-Jopling scheme

This scheme classifies leprosy on a scale from 'tuberculoid' to 'lepromatous' based on the clinical appearance and bacterial index of lesions (Lockwood 2002a). 'Tuberculoid' indicates that the body's immunity is good and there are few skin lesions. 'Lepromatous' means that the body has a poor immune response to the mycobacteria, and there is uncontrolled bacterial multiplication, many skin lesions, and also lesions in the mucosa of the nose and mouth. Peripheral nerve damage can occur at any point on the scale. Between the extremes of 'tuberculoid' and 'lepromatous' are the 'unstable borderline tuberculoid' and 'borderline lepromatous' forms (Lockwood 2002a).

WHO classification

This classification is based on the number of skin lesions (Britton 2004):

  • paucibacillary (PB) - up to five lesions

  • multibacillary (MB) - more than five lesions (or a positive smear at any site).

This is a simple classification scheme that makes treatment simpler for field workers, but it is less specific than the Ridley-Jopling scheme. The WHO classification system is the most widely used.

Impact

Nerve damage can happen before, during, and after chemotherapy treatment. It affects approximately 30% of people diagnosed with leprosy (2.6% with PB, 37% with MB, 2 years after diagnosis and MDT treatment) (Lockwood 2001). Data from 2002 showed that approximately 6% to 9% of people with newly-diagnosed leprosy presented with grade 2 disabilities (visible deformity or damage present), and as many as 20% to 56% of people have established nerve damage at diagnosis (Lockwood 2002b). These figures vary from country to country and between disease types.

Description of the intervention

As described above, leprosy is treated with multidrug chemotherapy. Other interventions, which we will not cover in this review, are aimed at treating immune reactions with corticosteroids, surgery, or both (Lockwood 2002).

The interventions of relevance to this review are those used in leprosy care which are aimed at the prevention and treatment of secondary damage to skin, nerves, and limbs. Such interventions include footwear, dressings (i.e., zinc tape, saline, iodine, gauze soaked in different ointments, dry dressings), self-care, and education (Lockwood 2002).

How the intervention might work

The rationale behind the use of, for example, appropriate footwear is to protect feet from secondary damage that can lead to superficial sores on the soles of the feet, and later ulcers and secondary infections (McDougall 2002). Many interventions may help in healing such ulcers (Srinivasan 1989).

Self-care includes daily management to reduce the effects of nerve function impairment (Lockwood 2002). Education, information, and empowerment of those affected by leprosy (and their carers) is part of some leprosy programmes (McDougall 2002).

As for dressings: ketanserin is an antihypertensive drug that is thought to decrease peripheral vascular resistance; this vasodilation might have beneficial effects on capillary haemodynamics, cause increased blood flow and enhance the healing of ulcers (Salazar 2001). Phenytoin is another topical dressing thought to enhance healing; the rationale behind this is that it "accelerates the formation and maturation of collagen fibres, stimulates fibroblast proliferation, and inhibits collagenase activity" (Bansal 1993). Zinc tape is also thought to enhance healing, as zinc might play a part in the healing of wounds; it remains intact when worn for a long period and tolerates moisture (Söderberg 1982).

Why it is important to do this review

An editorial note in WHO's Weekly Epidemiological Record says: "Leprosy control has benefited greatly from the implementation of MDT, which has enabled the disease to be cured and reduced the number of new G2D cases (with visible deformity or grade 2 disabilities); consequently stigma associated with leprosy and resultant discrimination against those affected has been reduced. There have also been economic benefits, with reduction of health system costs incurred for disability care, reconstructive surgery and rehabilitation. Nevertheless, surveillance of drug resistance, and research to develop shorter regimens and preventive agents, need to be continued or initiated in order to sustain the gains achieved and further reduce the disease burden due to leprosy" (WHO 2013).

"The key to effective management of leprosy is early diagnosis and treatment, and early recognition and management of nerve damage, combined with effective health education to prevent limb damage" (Lockwood 2002; Lockwood 2002a). Successful treatment of the nerve damage itself can be effective for preventing ulcer development. Corticosteroids have been used for this purpose (Lockwood 2002). However, a systematic review of three randomised controlled trials comparing prednisolone with placebo or comparing different doses of corticosteroids did not show a significant long-term effect (Van Veen 2007). Also, corticosteroids are not well tolerated by everyone and may cause harmful effects (Lockwood 2002). It is, therefore, still of importance to find the best way to prevent or treat skin damage.

People with leprosy are, after a few days on chemotherapy, no longer infectious and can lead a normal social life. This has contributed in recent years to the management of leprosy programmes worldwide moving away from clinics dedicated to the treatment of leprosy, to primary healthcare services in general (Lockwood 2002; WHO 2010). However, despite the opportunity to lead a normal social life, long-term nerve and muscle damage can lead to great psychosocial and financial difficulties, social stigmatisation, and decreased quality of life for people with leprosy. Care and awareness of limb use will in all circumstances be necessary, and education of those with leprosy is considered a central element to achieve a satisfactory level of self-care (Lockwood 2002). People with leprosy must be and are involved in all stages of the leprosy programme, which involves "detecting cases early...reducing stigma, and promotion of social integration" (WHO 2011).

Why we present a new protocol

We have made the decision to update our review which was published in 2008 (Reinar 2008), by way of a new protocol because we wanted to reduce the numbers of pre-specified outcomes to those that are most clinically relevant, and include both randomised controlled trials and quasi-randomised trials.

We will include randomised controlled trials and quasi-randomised controlled trials where the method of allocation is such as alternation, date of birth, or case record number (Higgins 2011 ). This deviates from the previous protocol (Reinar 2003) in which we stated that we would only include randomised controlled trials, but it is consistent with the designs we actually included in our review. In our published review (Reinar 2008) we identified and included three studies with an alternating allocation procedure, four randomised controlled trials and one study for which we could not determine whether the allocation procedure had been random or quasi-random.

The reason for including quasi-randomised trials was, and still is, that the risk of bias did not seem to be very different. According to Altman and Bland, quasi-random methods are "in principle unbiased - being unrelated to patients characteristics - problems arise from the openness of the allocation system" (Altman 1999). This point was somewhat elaborated by Chalmers (Chalmers 1999). As for randomised controlled trials, the results from a study by Pildal (Pildal 2005), revealed that of 96 studies not reporting on the concealment of the allocation procedure, only 15 (16%) actually had reported in the respective study protocols that concealment would be done. In the randomised studies that we included, none reported on concealment. On this basis, we assumed that most likely the randomised studies had not concealed allocation and so did not deviate from quasi-randomised trials in that respect. Consequently, they would all equally be prone to selection bias. Therefore, we chose to display the whole of the evidence base that had used these two designs, a decision we affirm in this protocol.

Objectives

To assess the effects of self-care, dressings, and footwear in preventing and healing secondary damage to the skin in persons affected by leprosy.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials. We will not include observational studies. Quasi-RCTs are defined as: trials with an allocation procedure such as alternation, date of birth or case record number.

Types of participants

Anyone with leprosy and potential damage to peripheral nerves who is on multidrug treatment or is post-treatment.

Types of interventions

Education, information, self-care programmes, dressings (i.e., zinc tape, saline, iodine, gauze soaked in different ointments, dry dressings), skin care, footwear, or other measures designed to prevent damage. Comparisons might be usual care, no interventions, or other interventions (for example other types of dressings, other types of footwear, other measures designed to prevent or treat damage).

Types of outcome measures

Primary outcomes
  1. Prevention of ulcer(s), as measured in the studies at six weeks, three months, six months, or one year or more.

  2. Healing of existing ulcer(s), as measured in the studies at six weeks, up to three months, up to six months, up to one year or more than a year (e.g. number of ulcers healed, size of ulcers, number of new ulcers).

  3. Adverse events, either those sufficiently serious to stop the intervention, or minor ones reported by participants.

Secondary outcomes
  1. Quality of life measures or other psychological or functional measures.

  2. Acceptability of treatment by person affected by leprosy.

  3. Cost of intervention as direct costs, if reported by study authors.

Tertiary outcome
  1. Prevention or treatment of other skin changes such as cracking, thickening or pigmentary changes

Search methods for identification of studies

We aim to identify all relevant RCTs and quasi-RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We will search the following databases for relevant trials:

  • the Cochrane Skin Group Specialised Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

  • MEDLINE via Ovid (from 1946);

  • EMBASE via Ovid (from 1974);

  • CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO);

  • AMED (Allied and Complementary Medicine Database); and

  • LILACS (Latin American and Caribbean Health Science Information Database).

We have devised a draft search strategy for RCTs and quasi-RCTs for MEDLINE (Ovid), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Trial registries

We will search the following trial registries using the term 'lepro*'.

Searching other resources

Unpublished and grey literature

We will search for unpublished and ongoing trials by corresponding with authors, field experts, and experts on tropical medicine or leprosy or both.

We will conduct a search for grey literature to identify studies not indexed in the databases listed above, using the following databases:

References from published papers

We will check the bibliographies of included studies and reviews for further references to relevant trials.

Adverse events

We will not perform a separate search for adverse effects of the target interventions. We will screen for reports of adverse events in the trials we read in full text. We will consider all adverse events reported in the included trials.

Data collection and analysis

Some parts of the methods section of this protocol use text that was originally published in other Cochrane reviews co-authored by KGB (predominantly Larun 2015).

Selection of studies

Two authors (LMR, LF) will independently screen all titles and abstracts identified in the literature searches for RCTs and quasi-RCTs. We will exclude studies that clearly do not have a trial design with random or quasi-random allocation of participants. Before inclusion or exclusion, the same two authors will independently read the full text of studies that we assess as eligible. A third researcher (KGB) will discuss any disagreement at this point, and decisions will be made by consensus. We will make judgments based on the inclusion criteria stated above (Criteria for considering studies for this review).

Data extraction and management

Two authors (LMR, LF) will independently perform the data extraction and enter data onto a data extraction form. One author (LMR) will enter data into Review Manager and one author (LF) will check the Review Manager file. We will not be blinded to the names of trial authors or journals.

Assessment of risk of bias in included studies

We will use Cochrane's 'Risk of bias' tool (Higgins 2011) to make judgments of low, high, and unclear risk of bias for the included studies. We will use the 'Risk of bias' tool on the RCTs and quasi-RCTs for all outcomes. We will also present the review authors’ judgment about each 'Risk of bias' item presented as a percentage across all included studies as a 'Risk of bias' graph.

We will assess selection bias by judging and reporting methods used for sequence generation and allocation concealment. Quasi-randomised trials will be judged as "high risk of bias" regarding sequence generation and concealment of allocation. Randomised trials not reporting on allocation concealment will be judged as "unclear".

We will assess performance bias by judging and reporting any blinding of participants, personnel, and outcome assessors. We will also look for and report any other threats to validity concerning systematic differences between groups in the care provided.

We will assess detection bias by judging and reporting any blinding of participants, personnel, and outcome assessors.

We will assess attrition bias by looking for systematic differences in loss to follow up between groups.

We will also look for and report other potential threats to validity concerning systematic differences between groups in how outcomes are determined. We will assess reporting bias (selective outcome reporting) by examining the methods section of the included study for mention of outcomes that are not reported later in the study or for outcomes that would have been expected to have been measured. For newer studies we will search for the protocols.

We will assess other risks of bias by judging and reporting, for example, avoidance of co-interventions, differences in baseline characteristics, recruiting bias, or inappropriate influence of funders.

We will not exclude studies at high risk of bias.

We will summarise 'Risk of bias' assessments for each key outcome for each study in a 'Risk of bias' summary table.

Measures of treatment effect

Dichotomous data

We will calculate the risk ratio (RR) and its 95% confidence interval (CI).

Continuous data

When all included studies use the same scale, we will calculate the mean differences (MDs) and their 95% CI, as it preserves the original units and is therefore easier to interpret. Where the included studies use different scales for the same outcome, we will calculate standardised mean differences (SMDs) to allow pooling. If some studies are based on change data and others on post-test data, we will include all studies in the same meta-analysis, with change data and endpoint data as subgroups.

Unit of analysis issues

Cluster randomised trials

Authors of cluster randomised trials may fail to account for the intraclass correlation co-efficient (ICC), leading to a 'unit of analysis' error; whereby CIs are unduly narrow and statistical significance overestimated (Divine 1992). If clustering is not accounted for in primary studies, we will seek to contact the corresponding author to obtain the ICC of their clustered data and adjust for this by using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (chapter 16.3). Otherwise we will present data in a table, with an asterisk (*) to indicate the presence of a probable unit of analysis error.

If cluster studies are appropriately analysed taking into account the ICC, and the report documents relevant data, synthesis with other studies will be possible using the generic inverse variance technique. In this case, we will present data adjusted for the clustering effect as if from a parallel-group randomised study, but we will perform sensitivity analysis in which we exclude such studies.

Multiple levels of intensity

One study may address the effects of the same intervention with different levels of intensity (e.g. frequency of follow-up). In the case of dichotomous outcomes we will sum up the sample sizes and the number of people with events across all relevant intervention groups. For continuous outcomes, we will combine means and standard deviations using methods described in chapter 7 (section 7.7.3.8) of the Cochrane Handbook (Higgins 2011).

Multiple interventions

Studies may also combine several interventions with one comparison group. In this case, we will analyse the effects of each intervention group versus the comparison separately, but divide the total number of participants in the comparison group. In the case of continuous outcomes the total number of participants in the comparison group will also be divided, but the means and standard deviations will be left unchanged (see chapter 16, section 16.5.4 in Higgins 2011).

Randomised cross-over trials

If we find and include randomised cross-over trials we will analyse data from the first period only.

Dealing with missing data

We will carry out analyses of all outcomes of interest according to the participants' allocated treatment irrespective of whether they received that treatment or not. For studies published in the last ten years we will contact authors to ask for data. We will not attempt to impute missing data.

Assessment of heterogeneity

If we judge that the included trials are too clinically heterogeneous to warrant a formal meta-analysis, we will not perform a meta-analysis but instead present the results of the included trials in a narrative format.

We will assess statistical heterogeneity on the basis of the Cochrane Handbook for Systematic Reviews of Interventions recommendations (Higgins 2011) (I² values of 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% may represent considerable heterogeneity).

In addition to the I² value (Higgins 2011), we will present the Chi² statistic and its P value and consider the direction and magnitude of the treatment effects. As in meta-analyses with few studies (Higgins 2011), the Chi² test is underpowered to detect heterogeneity should it exist; a P value of 0.10 is used as a threshold of statistical significance.

Assessment of reporting biases

We will consider the potential impact of publication bias on the results of the review. We will do a thorough search and attempt to obtain unpublished results to minimise the risk of publication bias. Funnel plots will be presented if more than 10 studies are included in any meta-analysis.

Data synthesis

We will present in a narrative format the results of those trials we assess to be too heterogeneous to combine. If we include trials with sufficient clinical and methodological similarity, we will estimate the effect across studies by using a random-effects model.

Where results are estimated for individual studies with low numbers of outcomes (< 10 in total) or where the total sample size is less than 30 participants and a risk ratio is used, we will report the proportion of outcomes in each treatment group together with a P value from a Fisher’s Exact test.

Subgroup analysis and investigation of heterogeneity

If we have sufficient data, we will consider doing subgroup analyses according to the study’s classification of disease severity, for example studies including paucibacillary cases or multibacillary cases only will be contrasted with studies including both paucibacillary and multibacillary cases.

Sensitivity analysis

We will perform sensitivity analysis for pooled results separately by addressing the effects on the results of excluding:

  • studies assessed as being at high risk of bias;

  • quasi-randomised trials; and

  • cluster-randomised trials.

'Summary of findings' table

We will use the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to assess the quality of the body of evidence. We will produce 'Summary of findings' tables presenting the overall quality of the evidence for primary outcomes for each comparison. We will judge the quality of the evidence as high, moderate, low, and very low (Higgins 2011, chapter 11).

Acknowledgements

The review authors thank the Cochrane Skin Group editorial base and the peer referees for their support and advice during the preparation of the protocol for this review.

The Cochrane Skin Group editorial base wishes to thank Sam Gibbs, who was the Dermatology Editor for this protocol; Matthew Grainge and Sonia Ratib, who were the Statistical Editors; Ching-Chi Chi, who was Methods Editor; the clinical referee, Einar Wilder-Smith; and the consumer referee, José Ramirez, Jr.

Diana NJ Lockwood contributed to writing the protocol, drafting the clinical sections of the background and responding to the clinical comments of the referees.

Appendices

Appendix 1. MEDLINE (Ovid) draft search strategy

1. exp Leprosy/
2. (lepro$ or lepra).tw.
3. hansen$.tw.
4. comparative.ti,ab.
5. randomized controlled trial.pt.
6. controlled clinical trial.pt.
7. randomized.ab.
8. placebo.ab.
9. clinical trials as topic.sh.
10. randomly.ab.
11. trial.ti.
12. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13. exp animals/ not humans.sh.
14. 12 not 13
15. 1 or 2 or 3
16. 14 and 15

Contributions of authors

Liv Merete Reinar was the contact person with the editorial base.
Liv Merete Reinar co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
Liv Merete Reinar and Kjetil Brurberg and Louise Forsetlund worked on the methods sections.
Liv Merete Reinar and Louise Forsetlund drafted the clinical sections of the background and responded to the clinical comments of the referees.
Kjetil G Brurberg, Louise Forestlund and Liv Merete Reinar responded to the methodology and statistical comments of the referees.
All authors contributed to writing the protocol.
Linda Lehman was the consumer co-author and checked the protocol for readability and clarity. She also ensured that the outcomes are relevant to consumers.
Liv Merete Reinar is the guarantor of the final review.

Disclaimer

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Skin Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service or the Department of Health.

Declarations of interest

Liv Merete Reinar: nothing to declare.
Louise Forsetlund: nothing to declare.
Kjetil G. Brurberg: nothing to declare.
Linda Faye Lehman: nothing to declare.

Sources of support

Internal sources

  • Norwegian Institute of Public Health, Norway.

    Provided paid time to work on the protocol.

External sources

  • The National Institute for Health Research (NIHR), UK.

    The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Ancillary