Cromoglicate Adjunctive Therapy for Outpatients With Schizophrenia

Study Overview
=================
Brief Summary
-----------------
This is a double blind adjunctive randomized controlled trial for schizophrenia using cromoglicate.

Detailed Description
-----------------
Schizophrenia (SZ) extracts a heavy personal and public health cost, primarily because there is no effective treatment. Though many drugs are currently available, the majority provide only partial relief for psychotic phenomena and none guarantee more than modest relief for 'negative symptoms' or for cognitive impairments. The Investigators must search for additional effective and safe medications. Recently, big data analytic strategies have yielded numerous 'repurposed' drugs, i.e., drugs with new indications that are already licensed for other uses. These strategies utilize massive data bases of known drug effects to find candidates that could predictably counteract known pathogenic effects of the disorder in question. Repurposed drugs are appealing not only because they have already been marketed and have known side effect profiles, but also because they have increased prior probability of efficacy. Still, careful randomized controlled trials (RCTs) are necessary for the new indications. The investigators have designed a systematic search for repurposed drugs likely to be beneficial for patients with SZ. Our novel search strategy began with the construction of a comprehensive protein-protein interaction network (PPI) for SZ using a validated method. Next, The Investigators searched public data bases for drugs that have predicted effects on multiple proteins in the SZ PPI network, but opposite to those observed in patients with SZ. The initial list was pruned using predetermined criteria, leaving 7 drugs of which cromoglycate (CGY) had the best negative correlation score. Reassuringly, three other drugs with lower scores in our list have already been tested for SZ. CGY is a safe and highly effective mast cell inhibitor that has been licensed for over 25 years for prophylaxis of asthma and allergies; it is also used to treat systemic mastocytosis and ulcerative colitis. Independent of our research, CGY is also predicted to stabilize the blood brain barrier (BBB), which can be disrupted in patients with SZ. Animal studies and favorable Log P estimates assure that CGY can cross the BBB. CGY has few reported side effects, despite its extensive use. Thus, multiple factors motivate our RCT. The Investigators propose a double blind adjunctive RCT for SZ using CGY. To maximize therapeutic benefits while minimizing risk and discomfort, The Investigators will enroll outpatients with SZ who meet criteria for residual positive symptoms after adequate trials of standard antipsychotic drug (APD) therapy (N=100, total). The Investigators will prefer patients in the early course of their illness. CGY or placebo will be added to prescribed medications for 4 weeks utilizing the Sequential Parallel Comparison Design to maximize power. The primary outcome will be improvement in positive symptoms as determined by the Positive and Negative Syndrome Scale (PANSS) positive symptom subscale. Secondary outcomes include total symptoms (PANSS total score), negative symptoms (PANSS negative symptom scale scores), cognition (Penn Computerized Neurocognitive Battery), and social function. Serum CGY levels will be monitored. The Investigators have proven experience with RCTs and the large number of patients are our clinical service ensures that recruitment targets will be fulfilled.

Official Title
-----------------
Cromoglicte Adjunctive Therapy for Outpatients With Schizophrenia

Conditions
-----------------
Schizophrenia, Schizo Affective Disorder

Intervention / Treatment
-----------------
* Drug: Cromoglycate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent. Both genders, ages 18-60 years Schizophrenia / schizoaffective disorder (DSM V). Treated with the same APD for at least 60 days; Stable dose of APD for > 1 month, continued throughout the study. PANSS total score of 60 and Score 4 or more on one or more items of the 'positive' syndrome items (P1-P7) Preference for patients with duration of psychosis less than 7 years. Exclusion Criteria: No illicit substance use in last 30 days/no dependence in 6 months with the exception of methadone treatment for opioid withdrawal. History or current medical /neurological illnesses that may lead to an unstable course with the exception of epilepsy which is well-controlled on an antiepileptic medication for at least 6 months. Pregnancy. History of immune disorders, HIV infection, or receiving immune-suppressants or immuno-modulators, e.g., steroids. Current or prior treatment with CGY or History of hypersensitivity to CGY. Intellectual disability as defined in DSM V.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This study will be a randomized placebo-controlled sequential parallel comparison design (SPCD).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cromoglycate<br>Cromoglycate nasal spray | Drug: Cromoglycate<br>* Cromoglycate will be administered intranasally (nasal spray) (1 spray each nostril 4 times a day, 5.2 mg/spray<br>* Other names: NasalCrom;Drug: Placebo<br>* Normal saline nasal spray will be administered intranasally (nasal spray) (1 spray each nostril 4 times a day, 5.2 mg/spray)<br>* Other names: Saline Nasal Spray;|
| Placebo Comparator: Placebo<br>Saline nasal spray | Drug: Cromoglycate<br>* Cromoglycate will be administered intranasally (nasal spray) (1 spray each nostril 4 times a day, 5.2 mg/spray<br>* Other names: NasalCrom;Drug: Placebo<br>* Normal saline nasal spray will be administered intranasally (nasal spray) (1 spray each nostril 4 times a day, 5.2 mg/spray)<br>* Other names: Saline Nasal Spray;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in positive symptoms | Clinical Severity as determined by the Positive and Negative Syndrome Scale (PANSS) positive symptom subscale. The PANSS is a standardized, clinical interview that rates the presence and severity of positive and negative symptoms, as well as general psychopathology for people with schizophrenia within the past week. Symptom severity for each item is rated according to which anchoring points in the 7-point scale (1 = absent; 7 = extreme) best describe the presentation of the symptom. 7 Items, (minimum score = 7, maximum score = 49) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Symptoms | Clinical Severity as determined by the Positive and Negative Syndrome Scale (PANSS) positive symptom subscale. The PANSS is a standardized, clinical interview that rates the presence and severity of positive and negative symptoms, as well as general psychopathology for people with schizophrenia within the past week. Symptom severity for each item is rated according to which anchoring points in the 7-point scale (1 = absent; 7 = extreme) best describe the presentation of the symptom. 30 Items, (minimum score = 7, maximum score = 210) | 12 weeks | 
| Negative Symptoms | Clinical Severity as determined by the Positive and Negative Syndrome Scale (PANSS) positive symptom subscale. The PANSS is a standardized, clinical interview that rates the presence and severity of positive and negative symptoms, as well as general psychopathology for people with schizophrenia within the past week. Symptom severity for each item is rated according to which anchoring points in the 7-point scale (1 = absent; 7 = extreme) best describe the presentation of the symptom. 7 Items, (minimum score = 7, maximum score = 49) | 12 weeks | 
| Cognition | As measured by the Penn Computerized Neurocognitive Battery (CNB) | 12 weeks | 
| Sheehan's disability scale (SDS) | The SDS is a brief, 5-item self-report tool that assesses functional impairment in work/school, social life, and family life. Total score 0-30 (0 unimpaired, 30 highly impaired) | 12 Weeks | 
| Global Assessment of Function (GAF) | The Global Assessment of Functioning, or GAF, scale is used to rate how serious a mental illness may be. It measures how much a person's symptoms affect his or her day-to-day life on a scale of 0 to 100. | 12 weeks | 
| Quality of Life Scale (QOL) | Self-administered questionnaire designed for use in patients with chronic illnesses. 7-point Likert-type scale ranging from delighted (7) to terrible (1). Total scale score (possible range: 16 - 112) | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
schizophrenia, schizoaffective disorder, cromoglicate