Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy (IRD) and the main cause of hereditary blindness, with more than 1.5 million patients affected worldwide and a prevalence of 1:4000 people [1]. The term was coined by Donders in 1857 [2] and compounds a group of heterogeneous diseases characterized by a progressive degeneration of photoreceptors, starting with rods and eventually affecting cones as well. This is the mechanism responsible for the progressive loss of vision function [3].

RP can have bilateral or, less frequently, unilateral involvement and can occur isolated or as part of a syndrome [1,4,5]. It is caused by more than 3000 mutations in over 70 genes, creating a wide heterogeneity among patients with RP [6].

RP affects mainly the outer retina, but in the final stages of the disease, atrophy and damage ultimately affect the inner retina, including retinal ganglion cells [7]. Intrinsically photosensitive retinal ganglion cells (ipGCs) constitute a special type of photoreceptors within the retina that contain the melanopsin photopigment [8,9]. Although they represent less than 10% of the total ganglion cells, they play a key role in regulating the pupillary reflex, circadian photoentrainment, mood, and diverse cognitive functions [9-16]. Alterations in circadian rhythms, partially dependent on ipGC integrity, have been previously reported in different ocular diseases and blindness [17-22]. These patients usually do not properly receive light signals that ordinarily synchronize their internal circadian clock to the 24-hour day, causing sleep-wake cycle abnormalities and recurring blocks of days with severe insomnia and excessive daytime sleepiness [21]. This circadian clock impairment could ultimately affect the quality of life due to sleep disorders and could also involve cardiovascular problems or emotional disorders or trigger or accelerate the pathology progression in neurodegenerative diseases [7,23,24].

The few therapeutic options for patients with RP currently available in daily clinical practice just retard disease progression and are limited. There is no therapy nowadays that restores vision, so the prognosis is poor [3]. Because of the chronic nature of this disease and its disabling progression, there has been great interest in the development of new strategies to help patients cope with the social and psychological impacts of blindness.

Among nonpharmacological strategies aimed at slowing down the degenerating process are those that are based on light protection. Some pieces of evidence indicate that some hereditary pigmentary retinopathies are partly light dependent [25,26]. Violet (400-440 nm) and blue (440-500 nm) light constitute the lower wavelength of the visible spectrum, which carries the highest amount of energy per photon [27]. The possible role of short-wavelength light (SWL) in the photochemical damage to retinal tissue and retinal pigment epithelium (RPE) cells has been studied, with high-energy SWL (415-455 nm) being the most harmful to the eye (the second type of phototoxicity or blue-light hazard) [28-30]. Blue-violet light could cause oxygen-dependent retinal injury, acting on specific chromophores, and N-retinylidene-N-retinylethanolamine (A2E) is considered the most important target molecule. Reactive oxygen species (ROS) initiate the activity of cysteine-dependent proteases, ultimately leading to apoptosis and cell death [28,31-34]. Mitochondria from photoreceptors, retinal ganglion cells, and RPE cells are the main targets of blue light–associated oxygen free radicals [35-37]. Moreover, photophobia, a common unpleasant symptom in patients with RP, has been described to be caused primarily by SWL in its interaction with S-cones from the retina [38]. In addition, in experimental RP models, limiting SWL exposure by the application of optical filters has been demonstrated to slow retinal degeneration [39].

However, some studies have shown that longer blue wavelengths of the visible spectrum (465-495 nm) are essential for the circadian rhythm, pupillary reaction, color discrimination, and night vision [7,23,24,40-43]. Numerous studies have demonstrated their close association to circadian rhythm regulation, alertness, memory, and cognition [44,45]. Therefore, blue-light exposure could regulate the secretion of melatonin in the pineal gland through the retinal–suprachiasmatic nucleus (SCN)–pineal axis, modulating cortisol expression through the hypothalamic–pituitary–adrenal (HPA) axis or the autonomous nervous system [7,23,24,44]. These responses are driven primarily by intrinsically photosensitive retinal ganglion cells (ipGCs), which are more sensitive to 480 nm SWL and remain functional in late stages of the disease [7]. In contrast, melatonin suppression has a peak sensitivity of roughly 460 nm in humans, the same spectrum that has been shown to reset the circadian pacemaker and directly enhance alertness [46].

In consequence, evening SWL exposure in daily life may affect sleep, hormone release, and the circadian rhythm in patients with RP. In fact, it has been reported that wearing SWL-blocking glasses that virtually eliminate SWL is effective in improving sleep, the circadian rhythm, and mood. Three randomized controlled trials (RCTs) have demonstrated that SWL-blocking glasses bring about significant improvement in sleep quality in participants with insomnia [42,43,47].

Among pharmacological interventions, the trophic and antioxidant effects of vitamins or nutritional supplements have been evaluated in patients with RP to demonstrate a protective action on cone death [48-50]. Accumulating evidence indicates that melatonin therapy is a promising approach in the treatment of various ocular degenerative disorders (eg, age-related macular degeneration, diabetic retinopathy, and RP) since it can exert a protective effect against damage to RPE cells evoked by ROS, but it has also been reported to increase ROS-induced damage to photoreceptors and RPE cells [51-55].

Melatonin is an endogenous hormone that has been implicated in a variety of biological processes, including antioxidant, anti-inflammatory, and neuroprotective activities [56,57]. Melatonin is released from the pineal gland in a circadian fashion, which is controlled by the SCN. However, many other tissues and organs also synthesize melatonin. In the retina, it is mainly synthesized by photoreceptors and is involved in the modulation of neuronal activities. Its circadian production results in a high concentration at night and a low level during the day, although its amount is small compared to its pineal counterpart [7,51,58].

Oxidative damage has been proposed to be an important contributor to cone death in RP, and antioxidants may prevent cone damage in RP by reacting with free radicals produced during light absorption [59]. Melatonin behaves like synthetic mitochondria-targeted antioxidants, which are concentrated in the mitochondria at relatively high levels [51,58]. It exerts its antioxidant actions in the eye via several mechanisms, including direct ROS scavenging, stimulating antioxidant enzymes, improving the functioning of the mitochondrial electron transport chain (ETC), reducing the extent of electron leakage from the mitochondrial complexes, and improving the efficacy of other antioxidants. As mentioned before, mitochondria from photoreceptors, retinal ganglion cells, and RPE cells are the main targets of ROS produced by the ETC, and thus, melatonin may prevent mitochondrial damage in patients with RP [7,51,58,60,61].

However, it has also been demonstrated that daily administration of appropriately timed melatonin can synchronize the circadian clock [62-66] in patients with sleep disorders; its use is even recommended by the Standards of Practice Committee of the American Academy of Sleep Medicine [67]. The phase-shifting effects of melatonin are essentially opposite to those of light. It can phase-shift the endogenous circadian clock and, in the absence of light, entrain the sleep-wake and neuroendocrine rhythms (cortisol) [61]. Therefore, it is likely that OM may also be effective in sleep and circadian rhythm management in patients with RP. However, to the best of our knowledge, no previous RCT has investigated the potential additive benefits of adjunctive SWL-blocking glasses plus OM in improving sleep, perceived stress, and the circadian rhythm in patients with RP.

The aim of this study is to assess the efficacy of OM combined with SWL-blocking filters in patients with RP who have sleep disorders and stress compared to any intervention alone or no intervention. We hypothesized that both interventions would improve their sleep quality, reduce their perceived stress levels, and shift their circadian rhythm to morningness.

RP is the commonest of inherited retinal disorders, with a great economic impact and poor associated quality of life [68]. In addition, there is a lack of standard treatment with a good level of efficacy data, which brings a fruitful opportunity to add new knowledge and pursue evidence-based interventions.

The innovation in this study is based on a noninvasive approach—SWL-blocking filters combined with OM. This treatment protocol might represent a better option for patients with RP, especially those with moderate or severe RP, who present with greater functional disability, glare symptoms, and variations in cortisol, salivary α-amylase (sAA), and melatonin levels.

Although a few trials have assessed the efficacy of different vitamins and melatonin in visual and sleep pattern anomalies in patients diagnosed with RP, none of them used a similar combined therapy and even fewer focused on variations in cortisol, sAA, and melatonin levels or determined the impact of these interventions on psychological factors. This study aims to fill this gap in the literature by enhancing the level of evidence with a double-blind RCT that evaluates the benefits that OM combined with SWL-blocking filters may bring to patients with moderate or severe RP.

RP is accompanied by significant disability, greater dependency, and a decrease in the health-related quality of life, with increased rates of admission to institutional facilities [68-70]. It is also considered a public health issue and a primary cause of headaches, sleep disturbances, and increased rates of depression [71]. Patients with RP also face difficulties in performing daily activities and increased risk of cardiovascular, metabolic, and psychiatric disorders [68-70]. Productivity losses for patients with visual impairment are likely to be amplified in patients with RP because of the early age at onset, vision challenges at school, and loss of visual function without some type of rehabilitation during prime working years [68-70].

The annual cost of adult vision problems for the National Health Service (NHS) is around US $51.4 billion. Among adults with retinal diseases, the annual total health care costs were estimated to be US $7317 higher per patient with RP, increasing the community costs by around 2.5 times because of the number of years of blindness experienced [72].

SWL-blocking filters and OM have been playing an important role in the treatment of several kinds of retinal conditions and sleep disabilities [42,43,47,60,61,73]. Unlike other expensive treatments for sleep disorders, anxiety, and depression, SWL-blocking filters or OM may provide effective control of the human circadian clock through changes in the HPA axis or the retinal–SCN–pineal axis, which could be positively correlated with improvement in the quality of life and visual function disability.

Some studies suggest a multidisciplinary treatment program that includes specialists from different areas of expertise [74]. This program provides a combination of drug treatment and SWL-blocking filters with an adequate assessment of the grade of severity (via clinical assessment) and biochemical stress (by analyzing biomarkers) and determines the impact of psychological factors on patients with RP. It could be considered a good alternative for patients with moderate and severe RP who have not benefited from expensive therapies (eg, bionic eye or genetic therapy) individually. Therefore, in this study, we suggest mimicking a multidisciplinary treatment by combining treatments and analyzing the impact of biochemical and psychological factors on anxiety and sleep disability.

To date, therapeutic approaches for RP are restricted to slowing down the degenerative process; treating ocular complications, such as cataracts and macular edema; and helping patients cope with the social and psychological impacts of blindness. In addition, the evidence from RCTs on the visual protective effects of vitamins and nutritional supplementations in patients with RP is limited and in some cases contradictory. Moreover, as mentioned before, few studies on the effects of blocking SWL on visual discrimination capacity in patients with RP have been reported. In addition, in clinical practice, there is insufficient experience to recommend the use of optical absorbing filters, since their potential effects on regulating the human internal circadian (24-hour) clock in patients with RP are yet unknown.

For this reason, the intervention groups will consist of SWL blocking alone (SWL group), OM therapy alone (OM group), and SWL blocking plus OM therapy (SWL+OM group) in order to determine whether there is any summative effect. No intervention has been chosen for comparison to avoid performance bias and other biases related to loss of blinding in the trial. Therefore, as several treatments have been proposed to slow down the degenerative process and the current evidence from their results is still limited, no intervention as the control group is justified for this study.

This parallel-group RCT will be performed at a single institution, which is a tertiary referral hospital with an affiliated research institute (Institute of Applied Ophthalmobiology [IOBA], University of Valladolid). The retinal units in both institutions are highly specialized to manage inherited retinal dystrophies and other related retinal eye diseases. Additionally, the IOBA has a clinical trial unit that could help with the local ethical requirements for running a clinical trial and any oversight or external auditing of data that is needed.

There will be 4 parallel groups of patients. Recruitment will be facilitated by a local foundation for patients with retinitis pigmentosa called the Retina Castilla y León (ReCYL) and will be tightly supervised by an ophthalmologist with specialization in retinal degenerations. Figure 1 provides a summary of the clinical pathways.

A draft intervention protocol will be developed for each group, covering preintervention, intervention, postintervention, and discharge settings based on the literature. A steering committee comprising ophthalmologists, opticians, nurses, psychologists, and the research team will be created to develop these protocols. Additionally, 2 ophthalmology residents will be included. Finally, 1 patient with RP, who is the current president of the Federation of Inherited Retinal Dystrophies’ Associations, will be included in the steering committee. The steering committee members are experts in their respective fields and have used the existing literature (summarized in the Background and Rationale section) to inform the inclusion of the different interventions in the protocols. The draft intervention protocols are presented in Table 1. Although the choice of each intervention in these protocols will be informed by the literature [7,28,30,36,51,57,67,75-82] and expert consensus of the steering committee, the study will assess the efficacy of combined interventions in sleep disorders and stress control in a large group of patients with RP. Before the intervention period, all patients will be asked to complete sleep diaries for 2 weeks. In addition, patients in the intervention groups (SWL, OM, SWL+OM) must complete them during the intervention period (30 days). Patients from the SWL and SWL+OM groups will wear SWL-restricting goggles in bright-light conditions and when using light-emitting diode (LED) electronic devices for the 30 days of intervention. Patients from the OM and SWL+OM groups will take 3 pills of Circadin 2 mg (OM) every evening at 10:00 P.M. with a margin of 30 minutes before and after.

A preintervention time of 1.5 years will be necessary for recruitment, informed consent, eligibility screening, and baseline data collection. Next, patients will be randomized to 4 groups in a 1:1 ratio. The treatment groups will include SWL with or without the use of OM. The control group will include patients who are eligible for the study but not willing to be randomized to an intervention sleep and stress management pathway. When the intervention phase (4 weeks) is over, all patients will be followed up for 6 months via standard monitoring. Figure 2 provides a summary of the RCT timeline.

The study population will comprise patients aged 18-65 years with a history of moderate or severe RP with a grading severity scale score of >1 point according to Iftikhar et al’s [83] scoring criteria. Eligible patients who provide written informed consent will be randomized to 1 of the 4 study groups. Outcomes will be assessed at multiple time points: at baseline in the preintervention period; then at 1, 2, 3, and 4 weeks of the intervention period; and then at 6 months postintervention.

All patients will be provided with a leaflet with clear instructions at the baseline visit, and they will be asked to follow the guidelines throughout the 4-week follow-up period.

The protocol was reviewed by the local Institutional Review Board of the East Health Area of Valladolid (CASVE 21-520) and will be registered with ClinicalTrials when a start date is decided.

Informed consent will be obtained from each patient in the preintervention period, which must be signed, thumb-imprinted, or recorded by the patient and collected by a coached research assistant, when necessary.

Privacy and confidentiality will be guaranteed for each patient, and the study will be conducted in accordance with the principles of the Declaration of Helsinki.

Once the study enters the data reporting phase, the data sets used and analyzed during the study will be available from the corresponding author upon reasonable request. The protocol and results will be released on the ClinicalTrials website, as required upon study completion. Final study results will be published in a peer-reviewed, PubMed-indexed journal to reach health care professionals. The authors will also seek to present the study findings at relevant ophthalmic subspecialty society meetings. The Federación de Asociaciones de Retinosis Pigmentosa de España (FARPE) website will describe this project. Final findings and results will be published on this website for the general public, as well as disseminated through the FARPE social networking channels.

The aim of the implementation of this clinical trial is to find an innovative strategy that allows a holistic approach for patients with RP, focusing on slowing down the progression of the disease, if possible, and improving their quality of life, especially their mood problems as well as their sleep-wake rhythm disorders.

The use of optical filters blocking SWL in the daylight was chosen as an intervention because of its nature as a noninvasive strategy as well as its protective potential against retinal neurodegeneration and melatonin suppression, both of which are relevant in these patients.

One of the main known sources of blue light is sunlight, but the widespread use of high-brightness lights with LED technology had made an increasing contribution in the past decade. A significant part of the LED emission spectrum peaks at 450 nm, within the wavelength range of blue light. Thus, with the increasing popularity of blue-rich LED-blacklight display devices, such as smartphones and tablets, computer screens, and other commonly used devices, our eyes are exposed to more blue light than they were in the past [28,36,75,108].

In addition, shorter-wavelength blue light has been reported to play a pivotal role in glare disability, especially in patients with retinal dystrophies [38,76]. Photophobia occurs because RPE cells appear to be defective with regard to absorbing light and because a lack of photoreceptors makes the adaptation to different lighting levels difficult [38,76]. Several studies have shown that patients with RP present higher values of intraocular scattering and, therefore, a decreased visual discrimination capacity in comparison to healthy people [77,109-111].

However, although excessive blue light is theoretically harmful, some studies have shown that longer blue wavelengths of the visible spectrum (465-495 nm) are essential for the circadian rhythm, pupillary reaction, color discrimination, and night vision [7,23,24,40-43]. Therefore, optical SWL filters may offer interesting advantages in having a positive effect on the visual discrimination capacity and decreasing glare disability in patients with RP. Finally, they could also help in circadian rhythm regulation and modulate the spectral transmittance of SWL, protecting injured eyes from potential additional photochemical damage.

We have selected melatonin as an intervention because of its close relationship with and involvement in the regulation of circadian cycles and its antioxidant and anti-inflammatory potential.

Melatonin’s functions are either receptor dependent or receptor independent. The former includes circadian rhythm control and sleep regulation. There is a considerable body of evidence of melatonin regulating sleep in various sleep disorders [7,62-66]. In fact, melatonin appears as one of the most effective drugs for treating circadian rhythm sleep-wake disorders [67]. Aging, the presence of certain diseases (eg, primary degeneration of the autonomous nervous system and diabetic neuropathy, some types of neoplasms, Alzheimer disease), and certain drugs (eg, β-blockers, clonidine, naloxone, and NSAIDs) abolish the nocturnal production of melatonin and are associated with impaired sleep [7,61,79,81].

Melatonin acts via its own receptors (MT1, MT2) present at the SCN, which are members of the G protein–linked receptor family [61]. The phase-shifting effects of melatonin are essentially opposite to those of light. In humans, its sleep-promoting effects become significant about 2 hours after intake, similar to the physiological sequence at night. However, administration of melatonin during the daytime (when its endogenous levels are minimal) results in induction of fatigue and sleepiness in humans [79,81].

Thus, melatonin administration appears to be one of the most promising approaches, with long-term benefits, for circadian rhythm sleep disorders because it simultaneously treats sleep and wake state problems and, in addition, synchronizes other bodily rhythms so as to maintain the body’s internal temporal order and prevent internal desynchronization [67,79,81].

Although the receptor-independent functions of melatonin include the detoxification of ROS and other reactive molecules, the antioxidant action of melatonin can also be expressed by increasing the efficacy in preventing oxidative DNA damage [7,51,58,60,61].

In addition to its pleiotropic actions, melatonin possesses an advantage over other possible candidates due to its amphiphilic character, which enables it to enter any fluid, cells, or subcellular structures, including mitochondria. Conversely, melatonin exhibits poor pharmacokinetic properties (eg, limited oral bioavailability and short plasma half-life) and low subtype receptor selectivity [79,81]. The effective doses reported are between 0.5 and 10 mg without a clear dose-response relationship (Multimedia Appendix 1). This mainly reflects the large interindividual variability in melatonin bioavailability, which is well known in the published literature and is attributed to differences in first-pass metabolism (Multimedia Appendix 1).

The acute toxicity of melatonin, as seen in both animal and human studies, is extremely low [82]. Melatonin may cause minor adverse effects, such as headache, insomnia, rash, diarrhea, and nightmares [82]. In animals, a lethal dose for 50% of the subjects (LD50) could not be established; even 800 mg/kg body weight (high dose) was not lethal [100]. Studies on human subjects given varying doses of melatonin (1-6.6 g/day) for 30-45 days and followed with an elaborate battery of biochemical tests to detect potential toxicity have concluded that in addition to drowsiness, all findings were normal at the end of the test period [79,81,82].

In the same line as the previous Spanish RCT (EudraCT no: 2012-002436-82) with OM and patients with RP, we have considered that 6 mg of OM for 30-40 days will be a safe dose to reach the desired effects without causing side effects in our target population. In general, a dose between 0.2 and 10 mg has been considered a safe starting dose in most of the previous studies with OM [67,79,81,82].

Accumulating evidence indicates that melatonin has a protective effect against various ocular disorders, such as uveitis, diabetic retinopathy, glaucoma, and even optic neuritis, through different mechanisms of action [60,61,73,112-115]. The multifaceted role of melatonin in neuroprotection might imply that melatonin may possess the capacity to attenuate the harmful effects that occur in degenerative retinal diseases, such as RP. Daily administration of melatonin has been shown to delay the photoreceptor apoptotic loss in RP mice [53,116]. This evidence supports that a clinical trial using melatonin to at least delay cell loss in RP in humans might be beneficial. In this context, a Spanish RCT (EudraCT no: 2012-002436-82) with 6 mg of OM and patients with RP is ongoing. Thus, therapeutic treatments of eye diseases using melatonin alone or in combination with other strategies deserve serious investigation.

The possibility of synergy between the 2 strategies stems from the common point between them—their involvement in circadian rhythms. Glucocorticoid hormones, particularly cortisol, participate in the body’s homeostasis and stress responses and follow a circadian rhythm, exhibiting a predictable peak in the morning, with a typically sharp elevation 30 minutes to an hour after awakening [117-119], although one that is apparently more complex than the melatonin rhythm.

The sAA enzyme has been used as a marker for the sympathetic nervous system response [118,120,121] and, like cortisol, has been shown to respond to psychosocial stress [118]. As with melatonin and cortisol, sAA production exhibits a regular circadian pattern [118]. Under normal, steady-state conditions, high levels of cortisol tend to be associated with low levels of sAA and vice versa.

Synthesis of melatonin is affected by SWL, whereas cortisol production and sAA levels are modulated by both short- and long-wavelength light. Since light is a well-known stimulus for suppressing the synthesis of the hormone melatonin at night, it was considered important for this study to also understand how blocking SWL in bright-light conditions may prevent the suppression of melatonin, which could affect perceived stress, sleep quality, and the quality of life of patients with RP.

The limitations that may be encountered in the application of this clinical trial are likely to be related to the large phenotypic and genotypic variability found among patients with RP; the difficulties in recruiting patients who meet the eligibility criteria, especially those with enough visual acuity that allows them to use the filters; and the subjective nature of the results of the questionnaires. However, this could be overcome by a good baseline study that allows for proper analysis that considers possible confounding variables. However, a sleep-monitoring device could be used, such as second-generation multisensory sleep trackers, but their price would increase the cost of the study and there is still no validated device for this purpose, so for the time being, they have not been included in the study protocol [122].

Preservation of vision in retinal degeneration is one of the priorities of the World Health Organization Vision 2020 program. Clinical trials of melatonin in the context of controlling RP, for example, warrant serious consideration. Furthermore, positive results of such studies would not only benefit patients with various ocular disorders but also be particularly helpful in countries where the treatments are expensive and not easily accessible.

This protocol for a double-blind RCT aims to shed light on the benefits that OM combined with SWL-blocking filters might have for patients with moderate or severe RP in terms of disease progression and quality of life. The goal is that this protocol be replicated for future studies, applied to additional inherited retinal dystrophies, and potentially incorporated into clinical practice. Should this study demonstrate the superiority of the combined intervention versus no intervention, its findings may also help reduce the impact of sleeping disorders and negative psychological disorders on the quality of life of patients with RP and help them recover their self-autonomy.