Background and rationale {6a}
Cough as a symptom of respiratory infections is frequent in primary care and is one of the most common causes to seek medical advice in general practices (GP) [1]. Cough after an upper respiratory tract infection can be very bothersome and disabling in daily activities and has a significant impact on physical and psycho-social health, leading to impairment in quality of life (QoL) [2]. Post-infectious cough, also known as subacute cough, is defined as lasting between 3 to 8 weeks following an upper respiratory tract infection [3]. It results from a protracted inflammation of the bronchial mucosa after a viral infection, an epithelial damage with irritant-receptors laid open and/or a temporary bronchial hyper-responsiveness [3, 4]. The diagnosis is based on the patient’s clinical history, physical examination and exclusion of other causes such as chronic obstructive pulmonary disease (COPD) or asthma [5, 6].
Recommendations for the management of post-infectious cough in general practice are scarce and inconsistent [3, 4]. A previous systematic review and meta-analysis of randomized controlled trials (RCT) carried by our group provided a wide overview of treatment options for primary care patients with post-infectious cough and examined the patient-relevant benefits and potential harms of available therapies [7]. The review found only six RCTs assessing diverse treatment regimens, such as inhaled fluticasone propionate, inhaled budesonide, salbutamol plus ipratropium-bromide, montelukast, nociception-opioid-1-receptor agonist, codeine, and gelatine. Most of the studies included in the review had an unclear or high risk of bias [7]. None of the individual RCTs found clear patient-relevant benefits for patients with post-infectious cough lasting 3 to 8 weeks. Two RCTs assessed inhaled corticosteroids for post-infectious cough [8, 9]. Pornsuriyasak et al. [9] included a total of 30 patients and found no benefit of inhaled steroids on cough outcomes at all. The trial by Ponsioen et al. [8], which included 135 patients with cough lasting for 2 weeks or more, indicated a potential benefit of inhaled steroids on cough in the overall study population that was explained by beneficial effects in the non-smoker sub-group. However, the study included a relevant number of patients (n=44; 33%) without post-infectious cough (lasting less than 3 weeks) and did not report results for this group separately [8].
Clinical guidelines and recommendations on the use of inhaled corticosteroids are unclear [3, 4, 10]. A Cochrane review published in 2013 evaluated studies in which inhaled corticosteroids were tested in individuals with post-infectious or chronic cough [11]. A majority of the studies focused on patients with chronic cough and only two examined the benefits for post-infectious cough [11]. The authors concluded that no recommendation can be proposed due to the high heterogeneity and inconsistency of the studies and their results [11]. Additionally, an RCT in family practices in England found no benefit in terms of duration or severity of cough after a 5-day treatment with oral corticosteroids compared to placebo for adult patients with acute lower respiratory tract infection and without asthma [12]. Another RCT assessed the effectiveness of oral corticosteroids for patients with acute sore throat, 55.9% of which also reported a cough in the course of the illness. In this study, patients who received a single oral dose of 10mg of dexamethasone were not more likely at 24 hours to experience complete resolution of symptoms compared to patients on placebo [13].
Many of the symptoms in post-infectious cough are thought to be mediated by inflammatory processes that are also present in exacerbations of asthma or COPD [5, 6]. For these conditions, there is strong evidence that short-term oral corticosteroids provide patient-relevant benefits [14] and prednisone (tablets at a dose of 40 mg once daily for 5 to 7 days) is a well-established oral steroid for acute asthma or exacerbation of COPD [5, 6]. However, at present there is no established evidence-based treatment option for post-infectious cough, despite it being a very frequent condition. There is also considerable uncertainty regarding patient benefits from using inhaled or oral corticosteroids. The systematic search of our group did not identify any published RCT that assessed short-term use of oral corticosteroids for post-infectious cough [7] (we updated our search in October 2018 and still found no pertinent trial). We screened multiple study registries using the International Clinical Trials Registry Platform from the World Health Organization (last search June 2020) and again found no trial investigating the use of oral corticosteroids for post-infectious cough. One registered trial aimed to assess the efficacy of inhaled budesonide in adult patients with chronic cough (registration ID NCT02715167) and several other studies planned to assess the efficacy of corticosteroids in children with acute or chronic cough (registration ID ACTRN12616001713482; ChiCTR-TRC-13003182; ACTRN12611000589987). A well-conducted randomized placebo-controlled trial is needed to determine the benefits and harms of using oral corticosteroids to treat post-infectious cough in patients in primary care.
Objectives {7}
We will investigate whether a 5-day treatment with 40 mg (2 tablets of 20 mg) orally administered prednisone provides patient-relevant benefits for adults with post-infectious cough triggered by an upper respiratory tract infection and seeking care in adult primary care practices. We hypothesize that the prednisone treatment will be superior to placebo and improve patients’ cough-related QoL at 14 days from group allocation. This randomised placebo-controlled trial aims to assess whether the benefits and harms of a 5-day prednisone treatment differ from those of a 5-day course of placebo.
Trial design {8}
We designed a protocol for a 1:1 randomised, parallel-group, placebo-controlled, triple-blinded, multicentric superiority trial in a primary health care setting, with blinded patients, physicians and outcome assessors. Recruitment will take place in general practices in Switzerland and participants in both the prednisone and the control groups will be followed-up at different time points; first at day 7, then day 14 and day 28, and at 3 months from the time of randomization. This protocol follows the Standard Protocol Items: Recommendations for Interventional Trials, 2013 statement [15].
Methods: Participants, interventions and outcomes
Study setting {9}
Patients with post-infectious cough will be recruited by participating doctors in primary practices from cantons in the German speaking part of Switzerland. Patient recruitment will continue until the sample size is reached. A list of the general practices currently taking part in the study can be obtained from the Sponsor-Investigator. Study participants will be followed-up through phone calls carried by study research staff at the Clinical Trial Unit (CTU) at the University Hospital Basel.
Eligibility criteria {10}
In order to be eligible for the study, patients will have to fulfil all the inclusion criteria:
- age ≥ 18 years
- seeing a GP for a dry or productive post-infectious cough (3 to 8 weeks) after an upper respiratory tract infection
- able and willing to give informed consent by themselves.
The presence of any one of the following exclusion criteria will lead to patient’s exclusion from the study:
- hypersensitivity to prednisone or to one of the adjuvants in the drug’s composition
- known or suspected diagnoses associated with cough, such as pneumonia, allergic rhinitis, sinusitis, bronchial asthma, COPD, gastroesophageal reflux disease
- other chronic disease such as bronchiectasis, cystic fibrosis, cancer, tuberculosis, heart failure
- use of inhaled or oral corticosteroids within the last four weeks
- immunodeficiency / immunocompromised state (e.g. cancer chemotherapy, HIV infection)
- pregnancy/breastfeeding
- regular treatment known to be associated with cough (e.g. angiotensin-converting enzyme inhibitors)
- a documented diagnosis of glaucoma or osteoporosis in the GP’s patient health record
- history of fractures due to osteoporosis
- uncontrolled diabetes mellitus (as deemed by GPs who appraise whether the potential side effects of short-time corticosteroids on glucose levels exceed the hypothesised benefit on cough).
Who will take informed consent? {26a}
The OSPIC study will be advertised through posters and information leaflets displayed in the collaborating GP practices. Patients with post-infectious cough presenting to their GP will be told about the OSPIC trial and provided with a study leaflet, participant information sheet and a consent form by their GP. They will be invited by the GP to take part after being given full written and verbal explanations of the trial purpose, potential benefits and risks, and the procedures involved. Those who agree to join the study will be asked to provide written consent and will be screened against the full eligibility criteria described above. Participants will have sufficient time to ask questions and GPs will make sure to underscore that participation is voluntary and that declining to join the study does not influence in any way the standard of care provided to patients.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
During the informed consent process with the GP participants will be asked to give written permission for the storage and future use of the data resulted from the study. The health-related data will be stored in an anonymized way by using the participant’s code and can be analysed for the purposes of future research projects. No biological specimens will be collected for the purpose of the OPSIC study.
Interventions
Explanation for the choice of comparators {6b}
Patients in the control group will receive 10 placebo pills of 20mg (40mg of placebo). Placebo pills are described in detail in the next section. Placebo will be used as comparator in this study to prevent various biases (in particular as the primary endpoint is patient-reported). Potential implications on a limited applicability of the results are acknowledged and will be discussed in the study results publication. From an ethical point of view an inactive control (placebo) seems justified since there is no established therapy for post-infectious cough and because the symptoms resolve over time due to the natural course of the disease [7, 12].
Intervention description {11a}
The expected duration of participation in the study is around 3 months. This includes the day 0 (randomization) study activities, the treatment period of 5 days, and four follow-up phone calls. At the baseline visit (day 0) patients will receive pre-randomized identically looking, individually labelled medication glass jars with daily doses of 40 mg (2 tablets of 20 mg per dose) of visually identical prednisone or placebo pills. Patients in the intervention group will receive 10 white tablets of PREDNISON Galepharm Tabl 20 mg and be asked to take 2 pills orally once a day during breakfast for 5 days. take 2 placebo tablets once daily for 5 days. The placebo tablets match in appearance, diameter and height the intervention medication. These are manufactured by Apotheke Hotz (Küsnacht, Zürich, Switzerland) and 140 mg Lactose monohydrate, 68 mg microcristalline cellulose, 5 mg Croscarmellose sodium and 2 mg Magnesium stearate. Verbal and written instructions on how the drugs should be taken will be provided to the study participants.
Pharmacokinetic evidence suggests that a minimum dose of 20 mg prednisone daily is required for non-asthmatic patients to achieve an adequate anti-inflammatory effect [16]. We select a dose of 40mg (2 tablets of 20 mg) of prednisone which is well established as treatment in patients with acute asthma or exacerbation of a chronic obstructive lung disease [14]. A dose of 40mg of prednisone will ensure sufficient pharmacokinetic activity to be able to reveal a potential treatment effect in post-infectious cough. We select a treatment duration of 5 days since post-infectious cough is thought to be mediated by inflammatory processes comparable to those in exacerbations of asthma or COPD. For these conditions there is strong evidence that short-term oral corticosteroids for 5 days provide patient-relevant benefit without relevant harm [14].
Criteria for discontinuing or modifying allocated interventions {11b}
Due to the short intervention of 5 days, no treatment modifications are planned unless in the (unlikely) occasion of any side effects. Even though the likelihood is very low, Adverse Events (AE) such as allergic reactions to the study drug, psychotic, or pre-psychotic episode, or Serious Adverse Events (SAE), sepsis, venous thromboembolism, fracture, can occur [17]. In any of these cases the treatment will be stopped immediately. Medication will also be discontinued for other urgent reasons, such as pregnancy, a cancer diagnosis or an infection other than an upper respiratory tract infection.
Strategies to improve adherence to interventions {11c}
In order to facilitate adherence to the study intake schedule, participants are given a written medication guide. GPs will inform patients in depth on the importance to adhere to the 5-day medication for ensuring the effectiveness of treatment. They will emphasize the value to the trial conduct of participants’ availability for the follow-up phone calls. Furthermore, the dosing schedule is very convenient as the drugs need to be taken only once a day during breakfast and for a clearly defined and limited timeframe. In the event of a missed dose, patients are instructed to continue to take the medication the next day. Adherence to the study procedures will be checked at the follow-up phone call on day 7 from randomization when research staff will ask participants about their medication intake. In case the study medication is prematurely stopped or discontinued patients are asked to return the empty drug glass jars to their GP. All these measures and participants’ specific details will be documented in the Case Report Form (CRF).
Relevant concomitant care permitted or prohibited during the trial {11d}
Apart from the use of corticosteroids, any co-treatment or co-medication (i.e. antitussives, inhalation, herbal teas, and homeopathic pharmaceuticals) is permitted. Any other medical intervention used by study participants will be recorded in the electronic Case Report Forms (eCRF) to analyse the potential influence on outcomes. Throughout the trial, participants’ medication can be re-evaluated by their GPs based on clinical needs. Cases may arise when the patients’ clinical condition is worsening or the patient presents to the GP for an additional consultation before the 5-day treatment is over. Treating doctors can independently decide to change to open-label treatment, adjust medication if they deem it necessary and for the benefit of their patients or choose additional therapeutic options. All participants will be asked at follow-up about concurrent medication, including if they started a treatment with antibiotics.
Provisions for post-trial care {30}
Corticosteroid potential side effects and complications will be systematically recorded from the time of randomization until the last follow-up call at 3 months. In case of persistent coughing at 3 months from randomization, the patient will be advised to visit the GP again for a new assessment and necessary further investigations. GPs and research staff are instructed to document time of onset, duration, resolution, actions to be taken, assessment of intensity and relationship with study treatment. An insurance covering the study activities is contracted through the Sponsor’s institution, the University of Basel.
Participants will be advised that they need to use contraceptives for the duration of the treatment and that they should inform the GP or the study team in case they suspect they have become pregnant. Women with anamnestic risk of a pregnancy (unprotected sexual intercourse in the last two weeks) shall be excluded from this study. If a participant will become pregnant during follow-up the participant will visit her gynaecologist. The GP will document the course and the outcome of the pregnancy.
Outcomes {12}
The primary outcome is the cough-related QoL at 14 days after randomization. We will use the validated Leicester Cough Questionnaire (LCQ) score [18-21] to assess the impact of the study medication on patients’ QoL (difference between arms measured 14 days after randomization). Total and individual LCQ domain scores will be calculated. The LCQ is also suitable for capturing longitudinal developments in cough and cough-related wellbeing, and can be useful in clinical trials assessing new medications for cough [20].
Secondary outcomes
On days 7, 14, and 28 and at 3 months patients will be called by trained and experienced research staff, and asked to complete the LCQ on the phone. Appointments for the next phone calls will be set during the previous phone call and will assess:
- Cough-related QoL assessed by the LCQ score at 7, 28 days and 3 months after randomisation,
- Cough-related QoL sub-domains physical, psychological, and social at 7, 14, 28 days and 3 months after randomisation,
- Overall cessation of cough at 7, 14, 28 days and 3 months after randomisation (binary variable yes/no),
- Incidence rate of re-consultations at GP and/or hospitalisations for potential illness deterioration and the occurrence of side effects within 3 months following randomisation.
The following safety outcomes will be captured:
· Incidence rate of re-consultations at GP and/or hospitalisations within 3 months following randomisation,
- Total AE within 3 months after randomization,
- SAE within 3 months after randomization,
- Changes in glucose levels for patients with pre-study controlled diabetes that are deemed by GP to exceed the hypothesized benefit on cough.
Incidence rates of AE and SAE will be assessed according to the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) [22] causality categories “certain”, “probable”, “possible”, and “unlikely” during 3 months following randomisation (further details in section 22).
Participant timeline {13}
General practitioners will enrol approximately 5 but not more than 10 participants from patients presenting for a consultation due to post-infectious cough (baseline visit) over a period of 18 months until the sample size is reached (N=204). Eligible patients who consent to the study will be randomly assigned (1:1) by their GP to the active treatment or the control group. At baseline the GP will decide what diagnostics are necessary and will complete an individual CRF with participant’s baseline socio-demographic information. If performed, the GP will also record diagnostic test results. Participants will be asked to complete the standardized LCQ questionnaire and hand it to the GP on day 0. Participants will also be informed about the follow-up calls and that the next telephone appointment will be at day 7 of the trial. After inclusion in the study it is at the discretion of the treating GP to re-assess each participant at the general practice, when and as often as clinically needed. Physical examinations, lab testing, performing X-rays (e.g. chest) or decisions to hospitalize patients, if indicated, can be carried by the GP.
Follow-up calls lasting around 15 minutes each are carried by research staff at the CTU, University Hospital Basel on days 7, 14, 28 and at 3 months after randomization. In case participants are not reached at the first call, follow-up phone calls will be performed several times and participants will be sent reminders by email. If participants are not reached for the follow-up calls at day 7, day 14 or day 28, then a call will be made in the next 2 days (day 7 +2, day 14 +2; day 28 +2). Participants will be called during the next 7 days (3 months +7 days) when research staff is unable to reach them at 3 months. At each follow-up, participants will be asked to complete the LCQ and answer other questions regarding cough status, side effects, concomitant therapy, cessation of cough, re-consultations/hospitalisation, AE, SAE. (Figure 1).
Sample size {14}
Sample size was estimated to have 80% power to detect the minimal clinically important difference (MCID) set at 1.3 points LCQ [23]. To be able to detect an MCID of 1.3 points with a power of 80%, a total of 204 patients need to be recruited for both arms. This was calculated without considering intra-patient correlation (IPC) correlation rho (ρ) between baseline and follow-up and without potential intra-cluster correlation (ICC) of patients treated by the same physician. To further increase power, we ignored ρ by calculating the sample size for a two-sample t-test with a two-sided alpha threshold of 5%. Due to the fact that the number of recruited patients per GP is limited to 10, ICC might remain small. We expect a drop-out rate of 10%, similar to that in the trial by Wang et al. [24]. Sample size estimation was based on the assumption that individual LCQ scores are normally distributed. Raj et al. [23] reported a standard deviation (SD) of 3.3 points. A recent trial with a design and study population similar to ours reported a SD of 2.9 [24]. We decided to use the more conservative assumption of 3.3 points. A less conservative choice of an SD of 2.9 and a ρ of 0.4, with the other parameters remaining the same, would have required a sample size of 120. Hence, we assume that by the conservative choice of SD and by neglecting ρ, our calculation will sufficiently compensate for loss of power due to ICC and drop-outs. To compute the t-test, the current version of the R language and environment (R Foundation, www.r-project.org) function “power.t.test” of the “stats” package was applied.
Recruitment {15}
A total of 204 eligible patients with post-infectious cough will be recruited from general practices in North-western and Central Switzerland within a period of approximately 18 months. The geographical area is large enough to recruit the required number of patients in the indicated timeframe as nearly 40% of adults can be affected by post-infectious cough after an acute respiratory infection [24, 25]. It is envisaged that the recruitment period will last 18 months: First-patient-in in autumn 2020 and last-patient-out in spring 2022. In case of recruitment difficulties due to scheduled numbers of participants not being reached at predefined milestones, the limit of maximum 10 randomized patients per GP can be increased. To include 204 participants the recruitment period will cover two winter seasons when the incidence of upper respiratory tract infection is very high and post-infectious cough is very common. Even though coughing is prevalent throughout the year and patients can be affected in summer as well, we expect that most participants will be enrolled during the cold months. In case of unforeseen difficulties leading to lower number of participants than reasonably expected after 9 months (less than 1/3 of the target study population is enrolled), the recruitment areas can be enlarged as the investigators have established cooperation with institutes of general medicine in the Eastern and the French speaking parts of Switzerland. If the enrolment goals are not met, the study will be submitted to other regional ethics committees in order to geographically expand the recruitment area.
Role of COVID-19
In January 2020, the respiratory disease outbreak caused by the novel coronavirus SARS-CoV-2 was declared a Public Health Emergency of International Concern by the World Health Organization [26, 27]. In the early stage of an infection with SARS-CoV-2 the most prevalent symptoms are fever and acute cough [28]. Therefore, patients with a SARS-CoV-2 infection have an acute cough (< 3 weeks duration) [29] and would not fulfil the inclusion criteria (cough lasting 3 to 8 weeks) for this trial. Further, patients with suspected SARS-CoV-2 infection in Switzerland are strongly recommended by the Federal Department of Public Health to directly present to specialized test centres and to avoid visiting their GPs [30]. Thus, it is unlikely that patients with COVID-19 would be suitable for inclusion in this study.
Assignment of interventions: allocation
Sequence generation {16a}
The randomization procedure will be implemented by the Clinical Trial Unit of the University Hospital Basel, which will generate a randomization list with a 1:1 treatment allocation. This list will be the basis for the University Hospital Basel Pharmacy to perform block randomization per practice, to label, and to pack the study medication in glass jars. All GP practices will receive pre-randomized identically looking medication packages which will be handed to participants in the order of reception. Following this procedure, participants will therefore be randomly allocated to either prednisone or placebo.
Concealment mechanism {16b}
With the randomization list being prepared by the CTU Basel and only accessible to the University Hospital Basel Pharmacy for preparing the sequentially numbered medication packages, the treatment allocation is concealed from patients, physicians, outcome assessors, and other involved personal.
Implementation {16c}
Participants will be enrolled by the GPs and will be assigned to the intervention randomly. GPs will distribute the randomized medication in the pre-established order set by the University Pharmacy Basel. For each medication package dispensed the GP will record at the time of randomization the individual participants’ code, the allocated medication label and the dispensation date in a drug accountability log. Participants are required to return unused investigational treatments to their GPs.
Assignment of interventions: Blinding
Who will be blinded {17a}
All GPs, clinical investigators, outcome assessors, and research staff involved in the study, as well as all patients, will remain blinded with respect to the randomisation throughout the trial. Participants in the study will receive identically looking medication jars with an accompanying guide stating that they are taking either placebo or prednisone tablets for a period of 5 days as part of the OSPIC study.
Procedure for unblinding if needed {17b}
In case participants require hospitalizations or they consult a different doctor (not their GP), they are encouraged to take the medication guide with them. GPs will not have access to the randomization list and in case of urgency they have to make an unblinding request with the OSPIC study team. In a next step, the OSPIC team (as soon as possible and during working hours) will request the unblinding from the CTU which will then break the code by using the study database secuTrial®. Each unblinding will be documented in the database’s integrated audit trail system.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Data acquisition will be performed at the baseline visit by GPs and will be captured with a study developed questionnaire (CRF) and the LCQ. The GP will record individual socio-demographic characteristics and medical history, including age, sex, smoking behaviour, information on household smoking, symptoms, current treatment and doctor consultations. If performed, the GP will also record diagnostic test results such as CRP test, white blood cell count, body temperature, blood pressure, pulse, oxygen saturation, previous or present X-Ray, previous or present lung function assessments. The LCQ is a validated QoL measurement tool for non-specific cough, developed for self-administration and takes 5 to 10 minutes to complete [18, 19]. It has a total score (addition of domain scores) that ranges from 3 to 21 points, with a higher score corresponding to better health status [19-21]. The LCQ has already been used in a similar randomized-controlled trial assessing the effectiveness of montelukast in the treatment of post-infectious cough [24]. It is short, easy to administer and assesses the impact of cough on various aspects of life, including emotions, sleeping behaviour, work and relationships. The LCQ contains 19 items divided over 3 domains: physical (8 items), psychological (7 items) and social (4 items); with a 7-point Likert scale [19, 20].
At baseline the GP will hand participants the LCQ and will be available to answer question. Participants will complete the LCQ on paper at baseline and over the telephone at follow-up. The LCQ questions will be asked by trained research staff from the CTU Basel at follow-up and recorded electronically. We will use the validated German version of the original LCQ [18]. Data collection forms can be obtained from the OSPIC trial Sponsor-Investigator.
Plans to promote participant retention and complete follow-up {18b}
Participants are encouraged by the GP to answer the follow-up questions posed by the research staff of the CTU Basel. If patients prematurely stop the study or do not answer the follow-up call, the study team can contact the GP to ask about possible GP visits, AE or SAE or hospitalizations (i.e. for pneumonia). Data will be collected until the time of withdrawal and will be analysed in the intention to treat analysis.
Data management {19}
All study data will be stored at the CTU, including the paper questionnaire completed by GP, which will be imported into an eCRF by trained study nurses and captured via a secuTrial© database based at the University Hospital Basel. In case the paper CRF raises queries, these will be resolved through inquiries with individual GP. Read-out CRF data will be formatted and merged with phone interview data into the eCRF. Direct access to source documents will be permitted for purposes of monitoring, audits and inspections. Study data entered in the eCRF are only accessible to authorized persons and an integrated audit trail will maintain a record of initial entries and any changes made, time and date of entry, and user name of the person authorizing the entry or change. The eCRF will be implemented by the data management group at the CTU of the University Hospital Basel.
Confidentiality {27}
Confidentiality will be guaranteed during the study by the Sponsor-Investigator who will ensure the study’s compliance with national and international data security. All study data will be coded by the GP, stored and analysed in a coded manner. Password protection and user right management is used for the eCRF and ensures that only authorised study personal, data managers and local authorities, when permissible by law and necessary, will have access to the data during and after the study. Participant contact information will be collected for carrying follow-up calls and will be filled in the paper CRF form by the GP. Only research staff conducting the follow-up interviews will have access to the participants’ contact data. Participant lists will be kept at the GP practices for the entire duration of the study. After the end of the study, the lists will be sent to the Sponsor-Investigator and included in the Investigator Site File (ISF). The ISF will be archived for 10 years according to International Conference on Harmonisation – Good Clinical Practice (ICH-GCP) [31]. The study team at the CTU will maintain a separate participant/contact list, which will be included into the ISF at the end of the study. All involved parties must keep the participant data strictly confidential.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable, no biological specimens are collected for the purposes of the OSPIC study.