Clozapine-induced Hypersalivation - Feasibility Trial
Condition: Sialorrhea
MeSH terms: Sialorrhea
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      A randomised placebo-controlled feasibility study of glycopyrrolate and hyoscine in the
      treatment of clozapine-induced hypersalivation to assess recruitment and retention rates in a
      multi-centre trial.
    

Detailed description: 
      Primary objective

      To assess the feasibility of recruiting both community and in-patients from different
      centres. Specifically, the feasibility study will:

        1. Ascertain whether the study design is acceptable to participants, including
           randomisation and use of telephone interviews.

        2. Ascertain whether the interventions are acceptable to participants and indicate likely
           attrition rates and tolerability.

      Secondary objective

      Ascertain the standard deviation of the daytime hypersalivation measure to estimate the
      required sample size for a future efficacy randomised clinical trial (RCT).

      Study design

      This is a multicentre (3 sites) randomised, double-blind, placebo-controlled feasibility
      study of glycopyrrolate and hyoscine in patients with clozapine-induced hypersalivation.
      Investigators will recruit 42 patients who have been prescribed clozapine and are
      experiencing hypersalivation. Eligible participants will be recruited to a 5-week study
      consisting of a 1-week wash-out period followed by a 4-week treatment period. Participants
      will be randomised on a 1:1:1 basis to one of three study arms (hyoscine, glycopyrrolate or
      placebo). Self-report measures of salivation and side effects will be taken weekly and
      cognition will be assessed on two occasions during the study.

      Identification, recruitment and consenting of participants

      Participants will be recruited from out-patient clozapine clinics from three National Health
      Service (NHS) mental health trusts. R&D approval will be obtained from each mental health
      trust prior to start of the study. The study protocol and information sheets will be provided
      to clinical staff at each participating site who will be asked to identify potential
      participants who fulfil inclusion/exclusion criteria. Clinical staff will approach potential
      patients and seek their agreement for research staff to approach them about participation in
      the study. After permission has been obtained to approach a potential participant, a
      researcher will write to them to send a study information. At least three days later, the
      researcher will contact the patient by telephone and enquire if they are interested in
      participation. If the patient provisionally agrees, an appointment will be made for the
      researcher to visit the participant (either at the participant's home or at their next clinic
      appointment), in order to answer any further questions the participant may have and to obtain
      written informed consent. Following recruitment and consent, the Responsible Clinician (RC)
      and the participant's General Practitioner (GP) will be informed in writing (with the
      participant's consent).

      Randomisation and blinding

      Randomisation to the three trial arms will be a 1:1:1 basis. The three arms are:

        -  Hyoscine (Arm A - treatment)

        -  Glycopyrrolate (Arm B - treatment)

        -  Placebo (Arm C - control)

      Neither the participant nor the researchers will be aware of the arm to which each
      participant has been allocated and details of the allocation will remain concealed from the
      research team until after data lock. Blinding of participants and the research team to
      allocation status will be assured by identical capsule appearance and identical labelling on
      trial medication (apart from labels identifying the patient). In the event a patient develops
      any side- effects where drug unblinding is required, the treating physician will be made
      aware of the study drug, possible side-effects and make the appropriate decision whether to
      continue or discontinue the drug. The safety and wellbeing of the patient will be paramount
      at all times.

      Participant withdrawal and replacement

      Participants who are removed from the study due to adverse events will be treated and
      followed according to accepted medical practice. The research team may withdraw a participant
      from trial because of:

        -  Adverse event or serious adverse event

        -  Withdrawal of consent

        -  Persistent non-compliance with the study protocol

        -  Sponsor's decision to terminate the study

        -  Withdrawal by the Investigator for clinical reasons not related to the study drugs

        -  Pregnancy

        -  Symptomatic deterioration including patients who experience rapid deterioration before
           completion of the protocol treatment.

      If a patient withdraws or is withdrawn from the study, it is not the intention to replace
      them.

      Study drug dosage

      Hyoscine. The dosing schedule for Hyoscine Hydrobromide during the 5-week study period is:
      week 1 - washout period (discontinue existing medication for clozapine-induced
      hypersalivation (CIH), if any); week 2 - 300 micrograms twice daily; weeks 3, 4 and 5 - 300
      micrograms three times daily. This is within the dose range recommended in the British
      National Formulary (BNF) (off licence use for hypersalivation), the Maudsley Prescribing
      Guidelines for the treatment of CIH and is consistent with current prescribing practice.

      Glycopyrrolate. The dosing schedule for Glycopyrronium Bromide during the 5-week study period
      will be: week 1 - washout period (discontinue existing medication for CIH, if any); week 2 -
      1 milligram twice daily; weeks 3, 4 and 5 - 1 milligram three times daily.

      Assessment measures

      Drooling Rating Scale (DRS) The DRS is a two-item scale comprising drooling severity and
      frequency assessments that combine to form a score ranging from 2 - 9. Whilst it has not been
      validated and its metrics (standard deviation, mean, sensitivity to change) are unknown in a
      CIH population, it has good face validity and has been used in published research on
      paediatric hypersalivation. A feasibility aim is to establish its metrics in a CIH
      population.

      Nocturnal Hypersalivation Rating Scale (NHRS) The NHRS is a validated single-item 5-point
      self-report scale for measuring the degree of nocturnal salivation that a respondent
      experiences. The NHRS is the only scale specifically mentioned in the Cochrane review for
      treatments for CIH that is recommended for inclusion in future studies of the efficacy of CIH
      interventions.

      Brief Assessment of Cognition in Schizophrenia (BACS) The BACS comprises a short battery of
      tests devised for easy administration and scoring which assess the extent of cognitive
      impairment in schizophrenia. The battery includes brief assessments of executive functions,
      verbal fluency, attention, verbal memory, working memory and motor speed and requires
      approximately 30 minutes to complete.

      Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) LUNSERS is a 51-item
      checklist of side-effects which asks for ratings on a 5-point scale of the degree to which
      respondents have experienced that side effect in the last month. It shows good reliability
      and validity, correlating well with other clinician-administered side effect scales. A
      modified LUNSERS will be used to assess side-effects in the previous week (rather than
      month).

      Data collection procedures

      There will be three visits in total by a researcher and there may also be one further visit
      to conduct an exit interview if a participant consents to this. The schedule of assessments
      is detailed in Table 1. A Baseline Visit will take place at the end of the Week 1 washout
      period, where a researcher will visit the participant at home to deliver trial medication for
      Week 2 and administer all assessment measures (DRS, NHRS, BACS, LUNSERS). The Maintenance
      Visit will take place at the end of Week 2, where a researcher will visit the participant at
      home to deliver trial medication for Weeks 3-5 and administer hypersalivation scales (DRS,
      NHRS) and the side effects scale (LUNSERS). The Final Visit will take place at the end of
      Week 5 where a researcher will visit the participant at home to administer all assessment
      measures (DRS, NHRS, BACS, LUNSERS) again.

      An important aim is to explore the feasibility of collecting information on hypersalivation
      and side-effects using weekly telephone calls assessing. At the end of Week 3 and Week 4, a
      researcher will telephone the participant at a prearranged time and administer
      hypersalivation scales (DRS, NHRS) and the side effects scale (LUNSERS).

      Researchers will request an exit interview with all participants who drop out of the study
      and a number of participants who complete the study until 12 interviews (4 from each study
      arm) have been conducted. Interviews will take place at the participant's home at their
      convenience Two researchers (one of whom will also be a service user) will conduct a
      20-minute interview to explore the participant's experience of taking part in the study,
      exploring the acceptability of the study methods and seeking advice on how study
      participation experience could be improved.

      Sample size considerations

      The intended sample size is based on recruiting sufficient numbers to fulfil the feasibility
      aims of the study. The intention is to recruit 14 patients to each of three study arms
      because recruitment for a total sample of 42 will allow a good estimate of recruitment and
      attrition rates. The investigators estimate an attrition rate of 20% (which is substantially
      higher than in previous studies) which implies nine dropouts and this allows clear
      differentiation from the progression criterion (40% drop-out, n=17), with >80% power to
      detect a difference of this size with the alpha 0.25 (1 tailed). This is consistent with the
      relaxed power and alpha criteria suitable for an early phase study of this type specifically
      the alpha 0.25 criterion. Furthermore, 14 in each arm will be sufficient to gain an
      indication of the metrics (standard deviation, mean, sensitivity to change) for the putative
      primary outcome measure (DRS) in placebo and active treatment arms recruited from this
      population for the future definitive study.

      Safety Reporting procedures

      All Adverse Events (AE) suspected of having a causal relationship to either study drug will
      be captured in the participant's clinical notes and Case Report Form (CRF) from the start of
      treatment (week 2) until the end of the patient's involvement in the study. Serious Adverse
      Events (SAE) will also be reported within 24 hours of observing or learning about the event.
      The study manager will liaise with the Chief Investigator (CI) to evaluate the event for
      seriousness, causality and expectedness. All SAEs will be followed-up until resolution and
      the participating site must provide follow-up reports if the SAE has not resolved at the time
      the initial report was submitted.

      Trial management and quality assurance

      The study is managed through the Trial Management Group (TMG) which includes those
      individuals responsible for the day-to-day management of the study. The TMG has operational
      responsibility for the conduct of the study including monitoring overall progress and taking
      appropriate action to safeguard participants and the quality of the study. The TMG will meet
      at least quarterly once the study is actively recruiting. At least annually, the TMG will be
      extended to invite an independent chair (not involved directly in the study) and additional
      independent members, a service user representative, and the assembly will be conducted as a
      Trial Steering Committee (TSC) meeting. The TSC takes responsibility for the scientific
      integrity of the study, the scientific validity of the study protocol, assessment of the
      study quality and conduct as well as for the scientific quality of the final study report.
      Decisions about the continuation or termination of the study or substantial amendments to the
      protocol are the responsibility of the TSC.
    

Intervention name(s): Hyoscine; Glycopyrrolate; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): 300 micrograms twice daily, increasing to 300 micrograms three times daily; 1 milligram twice daily, increasing to 1 milligram three times daily; Placebo twice daily, increasing to placebo three times daily
Other intervention name(s): hyoscine hydrobromide; glycopyrronium bromide
Intervention MeSH terms: Glycopyrrolate; Scopolamine; Bromides; Butylscopolammonium Bromide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: clozapine; hypersalivation; refractory schizophrenia